Isoxazoline hydroxamic acid derivatives as LpxC inhibitors

ABSTRACT

This invention pertains generally to compounds of Formula I and compositions containing such compounds, as well as methods of using such compounds to treat bacterial infections. In certain aspects, the invention pertains to methods and compositions for treating infections caused by Gram-negative bacteria.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 15/304,044, filedOct. 13, 2016, now allowed, which claims priority to InternationalApplication No. PCT/US2015/027009, filed Apr. 22, 2015, which claims thebenefit of priority to U.S. Provisional Application No. 61/982,467,filed Apr. 22, 2014, the contents of which are incorporated herein byreference.

FIELD OF THE INVENTION

This invention pertains generally to compounds and compositions andmethods for treating bacterial infections. In certain aspects, theinvention pertains to treating infections caused by Gram-negativebacteria. More particularly, the invention pertains to treatingGram-negative infections using compounds disclosed herein. Without beingbound by theory, the compounds are believed to act by inhibiting theactivity of UDP-3-O—(R-3-hydroxydecanoyl)-N-acetylglucosaminedeacetylase (LpxC). The invention includes compounds of Formula (I)which inhibit LpxC, pharmaceutical formulations containing suchinhibitors, methods of treating patients with such compounds andpharmaceutical formulations, and methods of preparing suchpharmaceutical formulations and inhibitors. The inhibitors can be usedto treat Gram-negative infections of patients. These compounds may beused alone or in combination with other antibacterials.

BACKGROUND OF THE INVENTION

Over the past several decades, the frequency of antimicrobial resistanceand its association with serious infectious diseases have increased atalarming rates. The increasing prevalence of resistant pathogens,especially as agents causing nosocomial infections, also calledhospital-acquired infections, is particularly disconcerting. Of the over2 million nosocomial infections occurring each year in the UnitedStates, 50 to 60% are caused by antimicrobial-resistant strains ofbacteria. The high rate of resistance to commonly used antibacterialagents increases the morbidity, mortality, and costs associated withnosocomial infections. In the United States, nosocomial infections arethought to contribute to or cause more than 77,000 deaths per year andcost approximately $5 to $10 billion annually. Among Gram-positiveorganisms, the most important resistant pathogens aremethicillin-(oxacillin-) resistant Staphylococcus aureus (MRSA),β-lactam-resistant and multidrug-resistant pneumococci, andvancomycin-resistant enterococci. Important causes of Gram-negativeresistance include extended-spectrum β-lactamases (ESBLs) in Klebsiellapneumoniae, Escherichia coli, and Proteus mirabilis, high-levelthird-generation cephalosporin (Amp C) 3-lactamase resistance amongEnterobacter species and Citrobacter freundii, and multidrug-resistancegenes observed in Pseudomonas, Acinetobacter, and Stenotrophomonas.

The problem of antibacterial resistance is compounded by the existenceof bacterial strains resistant to multiple antibacterials. For example,Pseudomonas aeruginosa isolates resistant to fluoroquinolones arevirtually all resistant to additional antibacterial medicines.

Thus there is a need for new antibacterials, particularly antibacterialswith novel mechanisms of action or novel chemical structures that avoidat least some of the prevalent resistance mechanisms. Much of theantibacterial discovery effort in the pharmaceutical industry is aimedat the development of drugs effective against gram-positive bacteria.

However, there is also a need for new Gram-negative antibacterials.Gram-negative bacteria are in general more resistant to a large numberof antibacterials and chemotherapeutic agents than are gram-positivebacteria.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds, pharmaceuticalformulations including the compounds, methods of inhibitingUDP-3-O—(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase (LpxC),and methods of treating Gram-negative bacterial infections.

In one aspect, the invention provides compounds of Formula (I), andcompositions containing these compounds, and methods of using thesecompounds and compositions for treating infections. Compounds of theinvention are generally of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

Z is N or CR¹, where R¹ is selected from H, halo, C₁₋₄ alkyl and C₁₋₄haloalkyl;

R² and R³ are independently selected from C₁₋₄ alkyl and C₁₋₄ haloalkyl,

R⁴ is H or C₁₋₄ alkyl;

X is selected from H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and CN;

L is selected from —C≡C—, —CR⁵═CR⁶—, —O—, —S—, and a direct bond betweenA and the ring containing Z;

R⁵ and R⁶ are independently selected from H, halo, C₁₋₄ alkyl, and C₁₋₄haloalkyl; and

A is halo, CN, or an optionally substituted group selected from C₁₋₄alkyl, C₃₋₆ cycloalkyl, phenyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-6 memberedheteroaryl containing up to four heteroatoms selected from N, O and S asring members, and 4-6 membered heterocyclyl containing up to twoheteroatoms selected from N, O and S as ring members,

-   -   wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, 5-6 membered heteroaryl containing up to four        heteroatoms selected from N, O and S as ring members, and 4-6        membered heterocyclyl containing up to two heteroatoms selected        from N, O and S as ring members are each optionally substituted        with up to three groups selected from halo, hydroxy, CN, R¹⁰,        —(CH₂)₀₋₂OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰, —S(O)(NH)R¹⁰, and        —(CH₂)₀₋₂N(R¹⁰)₂;        -   where each R¹⁰ is independently H or C₁₋₄ alkyl optionally            substituted with one or two groups selected from amino,            hydroxy, C₁₋₄ alkoxy, and CN; and —N(R¹⁰)₂ can represent a            5-6 membered heterocyclic ring optionally containing an            additional heteroatom selected from N, O and S as a ring            member, and optionally substituted with one or two groups            selected from oxo, halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy,            and amino.

Various embodiments of these compounds are described further herein.

In one aspect, the invention provides a method of inhibiting adeacetylase enzyme in Gram-negative bacteria, thereby affectingbacterial growth, comprising administering to a patient in need of suchinhibition a compound of formula I. In this and the following aspects ofthe invention, any species or subgenus of Formula I described herein canbe used.

In another aspect, the invention provides a method of inhibiting LpxC,thereby modulating the virulence of a bacterial infection, comprisingadministering to a patient in need of such inhibition a compound offormula I.

In another aspect, the invention provides a method to interfere withbiosynthesis of a bacterial outer membrane of a Gram-negative bacterium,which comprises contacting the bacterium with a compound of Formula I.

In another aspect, the invention provides a method for treating asubject with a Gram-negative bacterial infection comprisingadministering to the subject in need thereof an antibacteriallyeffective amount of a compound of formula I with a pharmaceuticallyacceptable carrier. In certain embodiments, the subject is a mammal andin some other embodiments, the subject is a human.

In another aspect, the invention provides a method of administering aninhibitory amount of a compound of formula I to fermentative ornon-fermentative Gram-negative bacteria. In certain embodiment of themethod of administering an inhibitory amount of a compound of formula Ito fermentative or non-fermentative Gram-negative bacteria, theGram-negative bacteria are selected from the group consisting ofPseudomonas aeruginosa and other Pseudomonas species, Stenotrophomonasmaltophilia, Burkholderia cepacia and other Burkholderia species,Alcaligenes xylosoxidans, species of Acinetobacter, Enterobacteriaceae,Haemophilus, Moraxella, Bacteroides, Fransicella, Shigella, Proteus,Vibrio, Salmonella, Bordetella, Helicobactor, Legionella, Citrobactor,Serratia, Campylobactor, Yersinia and Neisseria.

In another embodiment, the invention provides a method of administeringan inhibitory amount of a compound of formula I to Gram-negativebacteria, such as Enterobacteriaceae which is selected from the groupconsisting of organisms such as Serratia, Proteus, Klebsiella,Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea,Yersina and Edwardsiella species and Escherichia coli.

Another embodiment of the invention provides a pharmaceuticalcomposition comprising a compound of Formula I admixed with apharmaceutically acceptable carrier thereof. In some embodiments, thecomposition comprises an effective amount of the compound of Formula Ias described herein.

Pharmaceutical formulations according to the present invention areprovided which include any of the compounds described above and apharmaceutically acceptable carrier.

In some embodiments, the formulation comprises at least twopharmaceutically acceptable carriers or excipients.

Other aspects of the invention are discussed infra.

The present invention provides novel compounds, methods for inhibitingLpxC in Gram-negative bacteria, and novel methods for treating bacterialinfections. The compounds provided herein can be formulated intopharmaceutical formulations and medicaments that are useful in themethods of the invention. The invention also provides for the use of thecompounds in preparing medicaments and pharmaceutical formulations, foruse of the compounds in inhibiting LpxC, and for use of the compounds intreating bacterial infections in a subject.

The following abbreviations and definitions are used throughout thisapplication:

“LpxC” is an abbreviation that stands forUDP-3-O—(R-3-hydroxydecan-oyl)-N-acetylglucosamine deacetylase.

This invention is directed to compounds of Formula I and subformulaethereof, and intermediates thereto, as well as pharmaceuticalcompositions containing the compounds for use in treatment of bacterialinfections. This invention is also directed to the compounds of theinvention or compositions thereof as LpxC inhibitors. The compounds areparticularly useful in interfering with the life cycle of Gram-negativebacteria and in treating or preventing a Gram-negative bacterialinfection or physiological conditions associated therewith. The presentinvention is also directed to methods of combination therapy fortreating or preventing an Gram-negative bacterial infection in patientsusing the compounds of the invention or pharmaceutical compositions, orkits thereof in combination with at least one other therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

For purposes of interpreting this specification, the followingdefinitions will apply unless specified otherwise and wheneverappropriate, terms used in the singular will also include the plural andvice versa.

DEFINITIONS

Terms used in the specification have the following meanings:

As used herein, the term “subject” refers to an animal. In certainaspects, the animal is a mammal. A subject also refers to for example,primates (e.g., humans), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a human.

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disorder, ordisease, or a significant decrease in the baseline activity of abiological activity or process.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., slowing or arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In anotherembodiment “treating” or “treatment” refers to alleviating orameliorating at least one physical parameter including those which maynot be discernible by the patient. In yet another embodiment, “treating”or “treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers topreventing or delaying the onset or development or progression of thedisease or disorder.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

The term “antibacterial agent” refers to agents synthesized or modifiedin the laboratory that have either bactericidal or bacteriostaticactivity. An “active” agent in this context will inhibit the growth ofP. aeruginosa and/or other Gram-negative bacteria. The term “inhibitingthe growth” indicates that the rate of increase in the numbers of apopulation of a particular bacterium is reduced. Thus, the term includessituations in which the bacterial population increases but at a reducedrate, as well as situations where the growth of the population isstopped, as well as situations where the numbers of the bacteria in thepopulation are reduced or the population even eliminated. If an enzymeactivity assay is used to screen for inhibitors, one can makemodifications in bacterial uptake/efflux, solubility, half-life, etc. tocompounds in order to correlate enzyme inhibition with growthinhibition.

“Optionally substituted” means the group referred to can be substitutedat one or more positions by any one or any combination of the radicalslisted thereafter.

“Halo” or “halogen”, as used herein, may be fluorine, chlorine, bromineor iodine.

“C₁-C₆-Alkyl”, as used herein, denotes straight chain or branched alkylhaving 1-8 carbon atoms. If a different number of carbon atoms isspecified, such as C₆ or C₃, then the definition is to be amendedaccordingly, such as “C₁-C₄-Alkyl” will represent methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

“C₁-C₆-Alkoxy”, as used herein, denotes straight chain or branchedalkoxy having 1-8 carbon atoms. If a different number of carbon atoms isspecified, such as C₆ or C₃, then the edefinition is to be amendedaccordingly, such as “C₁-C₄-Alkoxy” will represent methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

“C₁-C₄-Haloalkyl”, as used herein, denotes straight chain or branchedalkyl having 1-4 carbon atoms with at least one hydrogen substitutedwith a halogen. If a different number of carbon atoms is specified, suchas C₆ or C₃, then the definition is to be amended accordingly, such as“C₁-C₄-Haloalkyl” will represent methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl that have at least onehydrogen substituted with halogen, such as where the halogen isfluorine: CF₃CF₂—, (CF₃)₂CH—, CH₃—CF₂—, CF₃CF₂—, CF₃, CF₂H—, CF₃CF₂CHCF₃or CF₃CF₂CF₂CF₂—.

“C₃-C₈-cycloalkyl” as used herein refers to a saturated monocyclichydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups includecyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. If a differentnumber of carbon atoms is specified, such as C₃-C₆, then the definitionis to be amended accordingly.

“4- to 8-Membered heterocyclyl”, “5- to 6-membered heterocyclyl”, “3- to10-membered heterocyclyl”, “3- to 14-membered heterocyclyl”, “4- to14-membered heterocyclyl” and “5- to 14-membered heterocyclyl”, refers,respectively, to 4- to 8-membered, 5- to 6-membered, 3- to 10-membered,3- to 14-membered, 4- to 14-membered and 5- to 14-membered heterocyclicrings containing 1 to 7, 1 to 5 or 1 to 3 heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulphur, which may besaturated, or partially saturated. The heterocyclic group can beattached at a heteroatom or a carbon atom. The term “heterocyclyl”includes single ring groups, fused ring groups and bridged groups.Examples of such heterocyclyl include, but are not limited topyrrolidine, piperidine, piperazine, pyrrolidine, pyrrolidinone,morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran,tetrahydropyran, 1,4-dioxane, 1,4-oxathiane, 8-aza-bicyclo[3.2.1]octane,3,8-diazabicyclo[3.2.1]octane, 3-Oxa-8-aza-bicyclo[3.2.1]octane,8-Oxa-3-aza-bicyclo[3.2.1]octane, 2-Oxa-5-aza-bicyclo[2.2.1]heptane,2,5-Diazabicyclo[2.2.1]heptane, azetidine, ethylenedioxo, oxtane orthiazole.

“Heteroaryl” is a completely unsaturated (aromatic) ring. The term“heteroaryl” refers to a 5-14 membered monocyclic- or bicyclic- ortricyclic-aromatic ring system, having 1 to 8 heteroatoms selected fromN, O or S. Typically, the heteroaryl is a 5-10 membered ring system(e.g., 5-7 membered monocycle or an 8-10 membered bicycle) or a 5-7membered ring system. Typical heteroaryl groups include furan,isotriazole, thiadiazole, oxadiazole, indazole, indazole, indole,quinoline, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or5-(1,2,4-triazolyl), 4- or 5-(1,2, 3-triazolyl), tetrazolyl, triazine,pyrimidine, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

The term “hydroxy” or “hydroxyl” includes groups with an —OH.

The term “a,” “an,” “the” and similar terms used in the context of thepresent invention (especially in the context of the claims) are to beconstrued to cover both the singular and plural unless otherwiseindicated herein or clearly contradicted by the context.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

The invention provides compounds of Formula (I) and various subgenerathereof as described herein, and methods of using these compounds totreat infections or inhibit bacterial growth or survival. The followingenumerated embodiments represent certain aspects of the invention:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Z is N or CR¹, where R¹ is selected from H, halo, C₁₋₄ alkyl and C₁₋₄haloalkyl;

R² and R³ are independently selected from C₁₋₄ alkyl and C₁₋₄ haloalkyl,

R⁴ is H or C₁₋₄ alkyl;

X is selected from H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and CN;

L is selected from —C≡C—, —CR⁵═CR⁶—, —O—, —S—, and a direct bond betweenA and the ring containing Z;

R⁵ and R⁶ are independently selected from H, halo, C₁₋₄ alkyl, and C₁₋₄haloalkyl; and

A is halo, CN, or an optionally substituted group selected from C₁₋₄alkyl, C₃₋₆ cycloalkyl, phenyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-6 memberedheteroaryl containing up to four heteroatoms selected from N, O and S asring members, and 4-6 membered heterocyclyl containing up to twoheteroatoms selected from N, O and S as ring members,

-   -   wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, 5-6 membered heteroaryl containing up to four        heteroatoms selected from N, O and S as ring members, and 4-6        membered heterocyclyl containing up to two heteroatoms selected        from N, O and S as ring members are each optionally substituted        with up to three groups selected from halo, hydroxy, CN, R¹⁰,        —(CH₂)₀₋₂OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰, —S(O)(NH)R¹⁰, and        —(CH₂)₀₋₂N(R¹⁰)₂;        -   where each R¹⁰ is independently H or C₁₋₄ alkyl optionally            substituted with one or two groups selected from amino,            hydroxy, C₁₋₄ alkoxy, and CN; and —N(R¹⁰)₂ can represent a            5-6 membered heterocyclic ring optionally containing an            additional heteroatom selected from N, O and S as a ring            member, and optionally substituted with one or two groups            selected from oxo, halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy,            and amino.

In selected embodiments of these compounds,

Z is N or CR¹, where R¹ is selected from H, halo, C₁₋₄ alkyl and C₁₋₄haloalkyl;

R² and R³ are independently selected from C₁₋₄ alkyl and C₁₋₄ haloalkyl,

R⁴ is H or C₁₋₄ alkyl;

X is selected from H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and CN;

L is selected from —C≡C—, —CR⁵═CR⁶—, —O—, —S—, and a direct bond betweenA and the ring containing Z;

R⁵ and R⁶ are independently selected from H, halo, C₁₋₄ alkyl, and C₁₋₄haloalkyl; and A is halo, CN, or an optionally substituted groupselected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and 4-6 membered heterocyclyl containing up to threeheteroatoms selected from N, O and S as ring members,

-   -   wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, and 4-6 membered heterocyclyl containing up to two        heteroatoms selected from N, O and S as ring members are        optionally substituted with up to three groups selected from        halo, hydroxy, CN, —OR, and —NR² where each R is independently H        or C₁₋₄ alkyl optionally substituted with one or two groups        selected from amino, hydroxy, C₁₋₄ alkoxy, and CN.

In some of these embodiments, A is halo, CN, or an optionallysubstituted group selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-6 membered heteroaryl such as pyridinyl,triazolyl, oxazolyl or thiazolyl, and 4-6 membered heterocyclylcontaining up to two heteroatoms selected from N, O and S as ringmembers, such as morpholine, piperidine, pyrrolidine, and piperazine.

Each of the compounds in Table A is a specific embodiment of theinvention.

2. The compound of embodiment 1 or a pharmaceutically acceptable saltthereof, wherein X is H or F.

3. The compound of embodiment 1 or 2 or a pharmaceutically acceptablesalt thereof, wherein R² is methyl.

4. The compound of any of embodiments 1-3 or a pharmaceuticallyacceptable salt thereof, wherein R³ is methyl.

5. The compound of any of embodiments 1-4 or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is H.

6. The compound of any of embodiments 1-5 or a pharmaceuticallyacceptable salt thereof, wherein Z is CH or CF.

7. The compound of any of embodiments 1-5 or a pharmaceuticallyacceptable salt thereof, wherein Z is N.

8. The compound of any of embodiments 1-7 or a pharmaceuticallyacceptable salt thereof, wherein A-L- is a group of the formula

where A is an optionally substituted group selected from C₁₋₄ alkyl andC₃₋₆ cycloalkyl, wherein A is optionally substituted with up to threegroups selected from halo, hydroxy, CN, —OR, and —N(R¹⁰)₂ where each R¹⁰is independently H or C₁₋₄ alkyl.9. The compound of embodiment 8 or a pharmaceutically acceptable saltthereof, wherein A is C₁₋₄ alkyl or cyclopropyl and is optionallysubstituted with F, OH, or OMe.10. The compound of any of embodiments 1-9, which is of the formula:

or a pharmaceutically acceptable salt thereof.11. A pharmaceutical composition, comprising:

the compound according to any of embodiments 1 to 10 or apharmaceutically acceptable salt thereof, and

a pharmaceutically acceptable carrier.

12. A pharmaceutical combination comprising:

a compound according to any of embodiments 1 to 10 or a pharmaceuticallyacceptable salt thereof,

an antibacterially effective amount of a second therapeutic agent, and

a pharmaceutically acceptable carrier.

13. The pharmaceutical combination composition according to embodiment12, wherein the second therapeutic agent is selected from the groupconsisting of Ampicillin, Piperacillin, Penicillin G, Ticarcillin,Imipenem, Meropenem, Azithromycin, erythromycin, Aztreonam, Cefepime,Cefotaxime, Ceftriaxone, Cefatazidime, Ciprofloxacin, Levofloxacin,Clindamycin, Doxycycline, Gentamycin, Amikacin, Tobramycin,Tetracycline, Tegacyclin, Rifampicin, Vancomycin and Polymyxin.14. A method of inhibiting a deacetylase enzyme in a Gram-negativebacterium, comprising:

contacting the Gram-negative bacteria with the compound according to anyone of embodiments 1 to 10 or a pharmaceutically acceptable saltthereof.

15. A method for treating a subject with a Gram-negative bacterialinfection, comprising:

administering to the subject an antibacterially effective amount of thecompound according to any one of embodiments 1 to 10, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

16. The method of embodiment 15, wherein the gram negative bacterialinfection is an infection comprising at least one bacterium selectedfrom the group consisting of Pseudomonas, Stenotrophomonas maltophila,Burkholderia, Alcaligenes xylosoxidans, Acinetobacter,Enterobacteriaceae, Haemophilus, Moraxella, Bacteroids, Fransicella,Shigella, Proteus, Vibrio, Salmonella, Bordetella, Helicobactor,Legionella, Citrobactor, Serratia, Campylobactor, Yersinia andNeisseria.17. The method of embodiment 16, wherein the bacterium is aEnterobacteriaceae which is selected from the group consisting ofSerratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella,Providencia, Morganella, Cedecea, Yersinia, and Edwardsiella species andEscherichia coli.18. A compound according to any one of embodiments 1 to 10 or apharmaceutically acceptable salt thereof, for use as a medicament.19. A compound according to any one of embodiments 1 to 10 or apharmaceutically acceptable salt thereof, for use in treatment of aGram-negative bacterial infection.20. A compound according to any one of embodiments 1 to 10 or apharmaceutically acceptable salt thereof, for use in treatment of aGram-negative bacterial infection, wherein the bacterial infection isselected from Pseudomonas aeruginosa, Stenotrophomonas maltophila,Burkholderia cepacia, Alcaligenes xylosoxidans, Acinetobacter,Enterobacteriaceae, Haemophilus, and Neisseria species.21. Use of the compound according to any one of embodiments 1 to 10 or apharmaceutically acceptable salt thereof, for the preparation of amedicament for the treatment of a Gram-negative bacterial infection in asubject, wherein the bacterial infection is selected from Pseudomonasaeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia,Alcaligenes xylosoxidans, Acinetobacter, Enterobacteriaceae,Haemophilus, and Neisseria species.22. The use of embodiment 21, wherein the bacterial infection is causedby an Enterobacteriaceae selected from the group consisting of Serratia,Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia,Morganella, Cedecea, and Edwardsiella species and Escherichia coli.

Compounds of the invention include each of the following, or anycombination thereof, and their pharmaceutically acceptable salts:

-   3-(3-(4-bromophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [1-A, 1-B]-   (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide    [2-A]-   3-(3-([1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [3-A, 3-B]-   3-(3-(4-(but-2-yn-1-yloxy)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [4-A, 4-B]-   3-(3-(4-cyclopropylphenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [5-A, 5-B]-   (R)-3-((R)-3-(4-(cyclopropylethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [6-A]-   3-(3-(4-(but-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [8-A, 8-B]-   N-hydroxy-3-(3-(4-(4-hydroxybut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide    [10-A, 10-B]-   3-(3-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [12A, 12 B]-   3-(3-(4-(cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [13-A, 13-B]-   N-hydroxy-2-methyl-2-(methylsulfonyl)-3-(3-(5-(prop-1-yn-1-yl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)propanamide    [14-A, 14-B]-   3-(3-(5-(cyclopropylethynyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [15-A, 15-B]-   3-(3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [16-A, 16-B]-   3-(3-(4-(cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [17-A, 17-B]-   (R)-3-((R)-3-(4-(4-fluorobut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    22-   (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-propylphenyl)-4,5-dihydroisoxazol-5-yl)propanamide    [23]-   (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-((E)-prop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide    [24]-   (R)-3-((R)-3-(4-((Z)-1-fluoroprop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide    [29]-   30.    (2R)—N-hydroxy-3-((5R)-3-(4-(5-hydroxyhexa-1,3-diyn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   31.    (R)-3-((R)-3-(4-ethylphenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   32.    (R)-3-((R)-3-(4-(ethylthio)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   33. (R)-3-((R)-3-(4-(3-fluoropropyl) phenyl)-4,    5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methyl sulfonyl)    propanamide-   34. (R)-3-((R)-3-(4-(4-fluorobutyl) phenyl)-4,    5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methyl sulfonyl)    propanamide-   39A. (R)—N-hydroxy-3-((R)-3-(4-(((1    r,3R)-3-(2-hydroxypropan-2-yl)cyclobutyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   39B. (R)—N-hydroxy-3-((R)-3-(4-(((1    s,3S)-3-(2-hydroxypropan-2-yl)cyclobutyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   40.    (R)—N-hydroxy-3-((R)-3-(4′-(2-hydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-   41.    (R)—N-hydroxy-3-((R)-3-(4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-   42.    (R)-3-((R)-3-(4-(3-fluoropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   43.    (R)-3-((R)-3-(4-(2H-1,2,3-triazol-2-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   44.    (R)—N-hydroxy-3-((R)-3-(4-((3-methoxycyclobutyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   45.    (R)—N-hydroxy-3-((R)-3-(4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-   46.    (R)—N-hydroxy-3-((R)-3-(4′-((S)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-   47.    (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-   48.    (R)—N-hydroxy-3-((R)-3-(4′-(2-methoxyethoxy)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   49.    (R)—N-hydroxy-3-((R)-3-(4′-((R)-1-hydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-   50.    (R)—N-hydroxy-3-((R)-3-(4′-(2-hydroxyethoxy)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-   51.    (2R)—N-hydroxy-3-((5R)-3-(4′-(2-hydroxy-1-methoxypropan-2-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   52.    (R)—N-hydroxy-3-((R)-3-(4-((3-(methoxymethyl)cyclobutyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   53.    (R)—N-hydroxy-3-((R)-3-(4-((3-(methoxymethyl)cyclobutyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   54.    (R)-3-((R)-3-(4-((3-fluorocyclobutyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)    propanamide-   55.    (R)-3-((R)-3-(4-((3-(cyanomethyl)cyclobutyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   56.    (R)—N-hydroxy-3-((R)-3-(4′-((S)-1-hydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-   57.    (R)—N-hydroxy-3-((R)-3-(3′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-   58. (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4′-(methyl    sulfonyl)-[1,1-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-   59.    (R)-3-((R)-3-(2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)-   60.    (R)—N-hydroxy-3-((R)-3-(4′-((R)-2-hydroxy-3-methoxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   61.    (R)—N-hydroxy-3-((R)-3-(4′-((R)-2-hydroxypropoxy)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   62.    (R)-3-((R)-3-(4-(but-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   64.    (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide-   65.    (R)—N-hydroxy-3-((R)-3-(4-(6-(hydroxymethyl)pyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   66.    (R)—N-hydroxy-3-((R)-3-(4-(6-methoxypyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   67.    (R)—N-hydroxy-2-methyl-3-((R)-3-(4-(6-methylpyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-(methylsulfonyl)    propanamide-   68.    (R)—N-hydroxy-2-methyl-3-((R)-3-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,    5-dihydroisoxazol-5-yl)-2-(methylsulfonyl)propanamide-   69.    (R)-3-((R)-3-(4′-(2-cyanopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   70.    (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-   71.    (R)-3-((R)-3-(4-(2-ethylpyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   72.    (2R)-3-((5R)-3-(4′-(1,2-dihydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   73.    (R)—N-hydroxy-3-((R)-3-(4′-(1-(hydroxymethyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   74.    (2R)—N-hydroxy-2-methyl-3-((5R)-3-(4′-(methylsulfinyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-(methylsulfonyl)    propanamide-   75.    (2R)—N-hydroxy-3-((5R)-3-(4′-(2-hydroxy-1-methoxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamidepropanamide    [-   76.    (2R)—N-hydroxy-2-methyl-3-((5R)-3-(4′-(S-methylsulfonimidoyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-(methylsulfonyl)propanamide-   77.    (R)-3-((R)-3-(4′-(2H-1,2,3-triazol-2-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   78.    (R)-3-((R)-3-(4-(pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   79.    (R)-3-((R)-3-(2′,6′-difluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   80.    (R)-3-((R)-3-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)    propanamide-   81.    (R)—N-hydroxy-3-((R)-3-(4-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   82.    (R)-3-((R)-3-(4-(3-chloropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   83.    (R)-3-((R)-3-(4-(4-fluoropyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   84.    (R)—N-hydroxy-3-((R)-3-(4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   85. (R)-3-((R)-3-(4-(3-methyl    pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   86.    (R)—N-hydroxy-3-((R)-3-(4′-((R)-3-hydroxy-2-methoxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   87.    (R)—N-hydroxy-3-((R)-3-(4′-(hydroxymethyl)-2′-methyl-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   88.    (R)-3-((R)-3-(2′,6′-difluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)    propanamide-   89.    (R)-3-((R)-3-(2′-fluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)    propanamide-   90.    (R)-3-((R)-3-(2′-methyl-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)    propanamide-   91.    (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(thiophen-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide-   92.    (R)—N-hydroxy-3-((R)-3-(4-(isothiazol-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   93.    (R)-3-((R)-3-(4′-((2S,3R)-2,3-dihydroxybutyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)    propanamide.-   94.    (R)-3-((R)-3-(4′-((S)-1,2-dihydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   95.    (R)-3-((R)-3-(4′-((R)-1,2-dihydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   96.    (2R)-3-((5R)-3-(4′-(1,3-dihydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   97.    (R)-3-((R)-3-(4-((4-((R)-1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-4,    5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)    propanamide-   98.    (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide-   99.    (R)-3-((R)-3-(4-((4-((S)-1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   100.    (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(3-(trifluoromethyl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide-   101.    (R)-3-((R)-3-(4-ethyl-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   102.    (R)-3-((R)-3-(2-fluoro-4′-(2-hydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)-   103.    (R)-3-((R)-3-(2-fluoro-4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   104.    (R)-3-((R)-3-(4′-(cyanomethyl)-2-fluoro-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   105.    (R)-3-((R)-3-(3-fluoro-4-(6-methoxypyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   107.    (R)-3-((R)-3-(2-fluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   108.    (R)-3-((R)-3-(3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   109.    (R)-3-((R)-3-(3-fluoro-4-(6-(hydroxymethyl)pyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   110.    (R)-3-((R)-3-(2-fluoro-4′-(2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   111.    (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(3-(trifluoromethyl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide-   112.    (R)-3-((R)-3-(3-fluoro-4-(2-isopropylpyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   113.    (R)-3-((R)-3-(2-fluoro-4′-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   114.    (R)-3-((R)-3-(2-fluoro-4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   115.    (R)-3-((R)-3-(2,2′-difluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   116.    (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(2,2′,6′-trifluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)    propanamide-   117.    (R)-3-((R)-3-(3-fluoro-4-(3-fluoropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   118.    (R)-3-((R)-3-(4-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   119.    (R)-3-((R)-3-(2-fluoro-4-(3-fluoropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   120.    (R)-3-((R)-3-(4-ethyl-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   121.    (R)—N-hydroxy-3-((R)-3-(4′-((R)-2-hydroxypropyl)-2-methyl-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide-   122.    (R)-3-((R)-3-(2,6-difluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide-   123.    (R)-3-((R)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)    propanamide.

The compounds of the invention may be synthesized by the generalsynthetic routes below, specific examples of which are described in moredetail in the Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure material.

Compounds of the present invention and intermediates can also beconverted into each other according to methods generally known to thoseskilled in the art.

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973, in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Third edition, Wiley, New York 1999, in“The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), AcademicPress, London and New York 1981, in “Methoden der organischen Chemie”(Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I,Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit,“Aminosäuren, Peptide, Proteine” (Amino acids, Peptides, Proteins),Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in JochenLehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate”(Chemistry of Carbohydrates: Monosaccharides and Derivatives), GeorgThieme Verlag, Stuttgart 1974. A characteristic of protecting groups isthat they can be removed readily (i.e. without the occurrence ofundesired secondary reactions) for example by solvolysis, reduction,photolysis or alternatively under physiological conditions (e.g. byenzymatic cleavage).

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known to those skilled inthe art. For example, salts of compounds of the present invention havingacid groups may be formed, for example, by treating the compounds withmetal compounds, such as alkali metal salts of suitable organiccarboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, withorganic alkali metal or alkaline earth metal compounds, such as thecorresponding hydroxides, carbonates or hydrogen carbonates, such assodium or potassium hydroxide, carbonate or hydrogen carbonate, withcorresponding calcium compounds or with ammonia or a suitable organicamine, stoichiometric amounts or only a small excess of the salt-formingagent preferably being used. Acid addition salts of compounds of thepresent invention are obtained in customary manner, e.g. by treating thecompounds with an acid or a suitable anion exchange reagent. Internalsalts of compounds of the present invention containing acid and basicsalt-forming groups, e.g. a free carboxy group and a free amino group,may be formed, e.g. by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g. with weak bases, or bytreatment with ion exchangers.

Salts can be converted into the free compounds in accordance withmethods known to those skilled in the art. Metal and ammonium salts canbe converted, for example, by treatment with suitable acids, and acidaddition salts, for example, by treatment with a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known to those skilled in the art into theindividual isomers; diastereoisomers can be separated, for example, bypartitioning between polyphasic solvent mixtures, recrystallisationand/or chromatographic separation, for example over silica gel or bye.g. medium pressure liquid chromatography over a reversed phase column,and racemates can be separated, for example, by the formation of saltswith optically pure salt-forming reagents and separation of the mixtureof diastereoisomers so obtainable, for example by means of fractionalcrystallisation, or by chromatography over optically active columnmaterials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like.

The following applies in general to all processes mentioned hereinbefore and hereinafter.

All the above-mentioned process steps can be carried out under reactionconditions that are known to those skilled in the art, including thosementioned specifically, in the absence or, customarily, in the presenceof solvents or diluents, including, for example, solvents or diluentsthat are inert towards the reagents used and dissolve them, in theabsence or presence of catalysts, condensation or neutralizing agents,for example ion exchangers, such as cation exchangers, e.g. in the H+form, depending on the nature of the reaction and/or of the reactants atreduced, normal or elevated temperature, for example in a temperaturerange of from about −100° C. to about 190° C., including, for example,from approximately −80° C. to approximately 150° C., for example at from−80 to −60° C., at room temperature, at from −20 to 40° C. or at refluxtemperature, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described under “Additional process steps”.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, methycyclohexane, or mixtures of those solvents, for exampleaqueous solutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds of the present invention, including their salts, may alsobe obtained in the form of hydrates, or their crystals may, for example,include the solvent used for crystallization. Different crystallineforms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4^(th) Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21).

The term “an optical isomer” or “a stereoisomer” refers to any of thevarious stereoisomeric configurations which may exist for a givencompound of the present invention and includes geometric isomers. It isunderstood that a substituent may be attached at a chiral center of acarbon atom. The term “chiral” refers to molecules which have theproperty of non-superimposability on their mirror image partner, whilethe term “achiral” refers to molecules which are superimposable on theirmirror image partner. Therefore, the invention includes enantiomers,diastereomers or racemates of the compound. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term isused to designate a racemic mixture where appropriate.“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R—Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line. Certaincompounds described herein contain one or more asymmetric centers oraxes and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possible isomers oras mixtures thereof, for example as pure optical isomers, or as isomermixtures, such as racemates and diastereoisomer mixtures, depending onthe number of asymmetric carbon atoms. The present invention is meant toinclude all such possible stereoisomers, including racemic mixtures,diasteriomeric mixtures and optically pure forms. Optically active (R)-and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. If the compoundcontains a double bond, the substituent may be E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration. All tautomeric formsare also intended to be included.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the present invention. “Salts”include in particular “pharmaceutically acceptable salts”. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compounds of thisinvention and, which typically are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds of the presentinvention. Isotopically labeled compounds have structures depicted bythe formulas given herein except that one or more atoms are replaced byan atom having a selected atomic mass or mass number. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C ¹⁵N, ¹⁸F ³¹P, ³²P,³⁵S, ³⁶Cl, ¹²⁵I respectively. The invention includes variousisotopically labeled compounds of the present invention, for examplethose into which radioactive isotopes, such as ³H and ¹⁴C, or those intowhich non-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labelled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F labeled compound of the presentinvention may be particularly desirable for PET or SPECT studies.Isotopically-labeled compounds of the present invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent previously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the present invention. The concentration ofsuch a heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the present invention that contain groups capable of actingas donors and/or acceptors for hydrogen bonds may be capable of formingco-crystals with suitable co-crystal formers. These co-crystals may beprepared from compounds of the present invention by known co-crystalforming procedures. Such procedures include grinding, heating,co-subliming, co-melting, or contacting in solution compounds of thepresent invention with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of the presentinvention.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

The present invention provides novel compounds, pharmaceuticalformulations including the compounds, methods of inhibitingUDP-3-O—(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase (LpxC),and methods of treating Gram-negative bacterial infections.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. Forexample, deuterium substitution at non-exchangeable hydrocarbon bonds(e.g., C—H) may retard epimerization and/or metabolic oxidation in vivo.

Isotopically-labeled compounds of the invention, i.e. compounds offormula (I), can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples and Preparations Sections using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously.

In another aspect, the invention provides a method of inhibiting adeacetylase enzyme in a Gram-negative bacterium, the method comprisingthe step of contacting the Gram-negative bacteria with a compound of theinvention, e.g., a compound of Formula I or salt thereof.

In still another aspect, the invention provides a method for treating asubject with a Gram-negative bacterial infection, the method comprisingthe step of administering to the subject in need thereof anantibacterially effective amount of a compound of the invention, e.g., acompound of Formula I or salt thereof with a pharmaceutically acceptablecarrier.

The compounds of the invention can be used for treating conditionscaused by the bacterial production of endotoxin and, in particular, byGram-negative bacteria and bacteria that use LpxC in the biosynthesis oflipopolysaccharide (LPS) or endotoxin.

The compounds of the invention also are useful in the treatment ofpatients suffering from or susceptible to pneumonia, sepsis, cysticfibrosis, wound, complicated diabetic foot or complicated urinary trackinfections and sexually transmitted diseases caused by Gram-negativepathogens. The compounds of the invention also are useful in theconditions that are caused or exacerbated by the bacterial production oflipid A and LPS or endotoxin, such as sepsis, septic shock, systemicinflammation, localized inflammation, chronic obstructive pulmonarydisease (COPD) and acute exacerbations of chronic bronchitis (AECB). Forthese conditions, treatment includes the administration of a compound ofthe invention, or a combination of compounds of the invention,optionally with a second agent wherein the second agent is a secondantibacterial agent or a second non-antibacterial agent.

For sepsis, septic shock, systemic inflammation, localized inflammation,chronic obstructive pulmonary disease (COPD) and acute exacerbations ofchronic bronchitis (AECB), preferred second non-antibacterial agentsinclude antiendotoxins including endotoxin receptor-binding antibodies,endotoxin-binding antibodies, antiCD14-binding protein antibodiesantilipopolysaccharide-binding protein antibodies and tyrosine kinaseinhibitors.

In treatment of serious or chronic respiratory tract infections, thecompounds of the present invention may also be used with secondnon-antibacterial agents administered via inhalation. Preferrednon-antibacterial agents used in this treatment includeanti-inflammatory steroids, non-steroidal anti-inflammatory agents,bronchiodilators, mucolytics, anti-asthma therapeutics and lung fluidsurfactants. In particular, the non-antibacterial agent may be selectedfrom a group consisting of albuterol, salbuterol, budesonide,beclomethasone, dexamethasone, nedocromil, beclomethasone, fluticasone,flunisolide, triamcinolone, ibuprofin, rofecoxib, naproxen, celecoxib,nedocromil, ipratropium, metaproterenol, pirbuterol, salneterol,bronchiodilators, mucolytics, calfactant, beractant, poractant alfa,surfaxin and pulmozyme (also called domase alfa).

The compounds of the invention can be used, alone or in combination witha second antibacterial agent for the treatment of a serious or chronicrespiratory tract infection including serious lung and nosocomialinfections such as those caused by Enterobacter aerogenes, Enterobactercloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca,Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia,Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumanii,Alcaligenes xylosoxidans, Flavobacterium meningosepticum, Providenciastuartii and Citrobacter freundi, community lung infections such asthose caused by Haemophilus influenzae, Legionella species, Moraxellacatarrhalis, Enterobacter species, Acinetobacter species, Klebsiellaspecies, and Proteus species, and infections caused by other bacterialspecies such as Neisseria species, Shigella species, Salmonella species,Helicobacter pylori, Vibrionaceae and Bordetella species as well as theinfections is caused by a Brucella species, Francisella tularensisand/or Yersinia Pestis.

A compound of the present invention may also be used in combination withother agents, e.g., an additional antibiotic agent that is or is not ofthe formula I, for treatment of a bacterial infection in a subject.

By the term “combination”, is meant either a fixed combination in onedosage unit form, or a kit of parts for the combined administrationwhere a compound of the present invention and a combination partner maybe administered independently at the same time or separately within timeintervals that especially allow that the combination partners show acooperative, e.g., synergistic, effect, or any combination thereof.

When used for treating Gram-negative bacteria, the compounds of thepresent invention can be used to sensitize Gram-negative bacteria to theeffects of a second agent.

An embodiment of the present invention is compounds of the presentinvention used in combination with a second antibacterial agent,non-limiting examples of antibacterial agents may be selected from thefollowing groups:

(1) Macrolides or ketolides such as erythromycin, azithromycin,clarithromycin, and telithromycin;

(2) Beta-lactams including penicillin such as penicillin G, penicillinV, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin,ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin,piperacillin, azlocillin, temocillin, cephalosporin such as cepalothin,cephapirin, cephradine, cephaloridine, cefazolin, cefamandole,cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin,cefinetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone,ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome,cefepime, and carbapenems such as carbapenem, imipenem, meropenem andPZ-601;

(3) Monobactams such as aztreonam;

(4) Quinolones such as nalidixic acid, oxolinic acid, norfloxacin,pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin,temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin,trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin,ganefloxacin, gemifloxacin and pazufloxacin;

(5) Antibacterial sulfonanmides and antibacterial sulphanilamides,including para-aminobenzoic acid, sulfadiazine, sulfisoxazole,sulfamethoxazole and sulfathalidine;

(6) Aminoglycosides such as streptomycin, neomycin, kanamycin,paromycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin,sisomicin, dibekalin and isepamicin;

(7) Tetracyclines such as tetracycline, chlortetracycline,demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline,tegacycline;

(8) Rifamycins such as rifampicin (also called rifampin), rifapentine,rifabutin, bezoxazinorifamycin and rifaximin;

(9) Lincosamides such as lincomycin and clindamycin;

(10) Glycopeptides such as vancomycin and teicoplanin;

(11) Streptogramins such as quinupristin and daflopristin;

(12) Oxazolidinones such as linezolid;

(13) Polymyxin, colistin and colymycin;

(14) Trimethoprim and bacitracin.

(15) Efflux pump inhibitors.

The second antibacterial agent may be administered in combination withthe compounds of the present inventions wherein the second antibacterialagent is administered prior to, simultaneously, or after the compound orcompounds of the present invention. When simultaneous administration ofa compound of the invention with a second agent is desired and the routeof administration is the same, then a compound of the invention may beformulated with a second agent into the same dosage form. An example ofa dosage form containing a compound of the invention and a second agentis a tablet or a capsule.

When used for treating serious or chronic respiratory tract infections,the compounds of the invention may be used alone or in combination witha second antibacterial agent administered via inhalation. In the case ofinhalation, a preferred second antibacterial agent is selected from agroup consisting of tobramycin, gentamicin, aztreonam, ciprofloxacin,polymyxin, colistin, colymycin, azithromycin and clarithromycin.

The language “effective amount” of the compound is that amount necessaryor sufficient to treat or prevent a bacterial infection and/or a diseaseor condition described herein. In an example, an effective amount of theLpxC inhibitor is the amount sufficient to treat bacterial infection ina subject. In another example, an effective amount of the LpxC inhibitoris an amount sufficient to treat a bacterial infection, such as, but notlimited to Pseudomonas aeruginosa and the like in a subject. Theeffective amount can vary depending on such factors as the size andweight of the subject, the type of illness, or the particular compoundof the invention. For example, the choice of the compound of theinvention can affect what constitutes an “effective amount.” One ofordinary skill in the art would be able to study the factors containedherein and make the determination regarding the effective amount of thecompounds of the invention without undue experimentation.

The regimen of administration can affect what constitutes an effectiveamount. The compound of the invention can be administered to the subjecteither prior to or after the onset of a bacterial infection. Further,several divided dosages, as well as staggered dosages, can beadministered daily or sequentially, or the dose can be continuouslyinfused, or can be a bolus injection. Further, the dosages of thecompound(s) of the invention can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

Compounds of the invention may be used in the treatment of states,disorders or diseases as described herein, or for the manufacture ofpharmaceutical compositions for use in the treatment of these diseases.The invention provides methods of use of compounds of the presentinvention in the treatment of these diseases or pharmaceuticalpreparations having compounds of the present invention for the treatmentof these diseases.

The language “pharmaceutical composition” includes preparations suitablefor administration to mammals, e.g., humans. When the compounds of thepresent invention are administered as pharmaceuticals to mammals, e.g.,humans, they can be given per se or as a pharmaceutical compositioncontaining, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) ofactive ingredient in combination with a pharmaceutically acceptablecarrier.

The phrase “pharmaceutically acceptable carrier” is art recognized andincludes a pharmaceutically acceptable material, composition or vehicle,suitable for administering compounds of the present invention tomammals. The carriers include liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting the subject agent from one organ, or portion of the body,to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the patient. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, α-tocopherol, and the like; and metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, inhalation, topical, transdermal, buccal, sublingual, rectal,vaginal and/or parenteral administration. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods well known in the art of pharmacy. The amount of activeingredient that can be combined with a carrier material to produce asingle dosage form will generally be that amount of the compound thatproduces a therapeutic effect. Generally, out of one hundred percent,this amount will range from about 1 percent to about ninety-nine percentof active ingredient, preferably from about 5 percent to about 70percent, most preferably from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluent commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc., administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administration is preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous and subcutaneousdoses of the compounds of this invention for a patient, when used forthe indicated analgesic effects, will range from about 0.0001 to about100 mg per kilogram of body weight per day, more preferably from about0.01 to about 50 mg per kg per day, and still more preferably from about1.0 to about 100 mg per kg per day. An effective amount is that amounttreats a bacterial infection.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical composition.

The compounds as defined in embodiments may be synthesized by thegeneral synthetic routes below, specific examples of which are describedin more detail in the Examples.

General Synthetic Schemes

A general method to synthesize compounds of Formula (I) is depicted inScheme A. The first step is to generate a nitrile oxide in situ fromaldoxime A-1, which then undergoes cycloaddition with an alkenesulfoneA-2 to provide isoxazoline A-3. The group -L-A on the phenyl/pyridinylring in compound A-4 could be incorporated by transition metal catalyzedreactions with a phenyl bromide or pyridyl bromide as shown in Step 2.The coupling reactions can be carried out by a variety of techniques,which will be readily apparent to those skilled in the art. The ester inA-4 can be converted to hydroxamic acid I via saponification of theethyl ester and amidation of the free acid withO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (THPONH₂), followed byde-protection of the THP under acidic conditions.

General Synthetic Procedures

Compounds of the present invention are prepared from commonly availablecompounds using procedures known to those skilled in the art, includingany one or more of the following conditions without limitation:

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group,” unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such ase.g., Science of Synthesis: Houben-Weyl Methods of MolecularTransformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp.(URL: http://www.science-of-synthesis.com (Electronic Version, 48Volumes)); J. F. W. McOmie, “Protective Groups in Organic Chemistry”,Plenum Press, London and New York 1973, in T. W. Greene and P. G. M.Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley,New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.Meienhofer), Academic Press, London and New York 1981, in “Methoden derorganischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4thedition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H. Jeschkeit, “Aminosäuren, Peptide, Proteine” (Amino acids,Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideund Derivate” (Chemistry of Carbohydrates: Monosaccharides andDerivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic ofprotecting groups is that they can be removed readily (i.e., without theoccurrence of undesired secondary reactions) for example by solvolysis,reduction, photolysis or alternatively under physiological conditions(e.g., by enzymatic cleavage). Salts of compounds of the presentinvention having at least one salt-forming group may be prepared in amanner known per se. For example, salts of compounds of the presentinvention having acid groups may be formed, for example, by treating thecompounds with metal compounds, such as alkali metal salts of suitableorganic carboxylic acids, e.g., the sodium salt of 2-ethyl hexanoicacid, with organic alkali metal or alkaline earth metal compounds, suchas the corresponding hydroxides, carbonates or hydrogen carbonates, suchas sodium or potassium hydroxide, carbonate or hydrogen carbonate, withcorresponding calcium compounds or with ammonia or a suitable organicamine, stoichiometric amounts or only a small excess of the salt-formingagent preferably being used. Acid addition salts of compounds of thepresent invention are obtained in customary manner, e.g., by treatingthe compounds with an acid or a suitable anion exchange reagent.Internal salts of compounds of the present invention containing acid andbasic salt-forming groups, e.g., a free carboxy group and a free aminogroup, may be formed, e.g., by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g., with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by, e.g., medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g., using chromatographic methods,distribution methods, (re-) crystallization, and the like.

General Process Conditions

The following applies in general to all processes mentioned throughoutthis disclosure. The process steps to synthesize the compounds of theinvention can be carried out under reaction conditions that are knownper se, including those mentioned specifically, in the absence or,customarily, in the presence of solvents or diluents, including, forexample, solvents or diluents that are inert towards the reagents usedand dissolve them, in the absence or presence of catalysts, condensationor neutralizing agents, for example ion exchangers, such as cationexchangers, e.g., in the H⁺ form, depending on the nature of thereaction and/or of the reactants at reduced, normal or elevatedtemperature, for example in a temperature range of from about −100° C.to about 190° C., including, for example, from approximately −80° C. toapproximately 150° C., for example at from −80 to −60° C., at roomtemperature, at from −20 to 40° C. or at reflux temperature, underatmospheric pressure or in a closed vessel, where appropriate underpressure, and/or in an inert atmosphere, for example under an argon ornitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described in Science of Synthesis: Houben-Weyl Methods ofMolecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofurane ordioxane, liquid aromatic hydrocarbons, such as benzene or toluene,alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, suchas acetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of those solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

In accordance with the foregoing the present invention provides in a yetfurther aspect: A pharmaceutical combination comprising a) a first agentwhich is a compound of the invention, e.g. a compound of formula I orany subformulae thereof, and b) a co-agent, e.g. a second drug agent asdefined above.

A method as defined above comprising co-administration, e.g.concomitantly or in sequence, of a therapeutically effective amount of acompound of the invention, e.g. a compound of formula I or anysubformulae thereof, and a co-agent, e.g. a second drug agent as definedabove.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time. Fixedcombinations are also within the scope of the present invention. Theadministration of a pharmaceutical combination of the invention resultsin a beneficial effect, e.g. a synergistic therapeutic effect, comparedto a monotherapy applying only one of its pharmaceutically activeingredients.

Each component of a combination according to this invention may beadministered separately, together, or in any combination thereof.

The compound of the invention and any additional agent may be formulatedin separate dosage forms. Alternatively, to decrease the number ofdosage forms administered to a patient, the compound of the inventionand any additional agent may be formulated together in any combination.For example, the compound of the invention inhibitor may be formulatedin one dosage form and the additional agent may be formulated togetherin another dosage form. Any separate dosage forms may be administered atthe same time or different times. Alternatively, a composition of thisinvention comprises an additional agent as described herein. Eachcomponent may be present in individual compositions, combinationcompositions, or in a single composition.

EXAMPLES

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The assays used throughoutthe Examples are accepted. Demonstration of efficacy in these assays ispredictive of efficacy in subjects.

General Synthesis Methods

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

LIST OF ABBREVIATIONS Ac acetyl ACN Acetonitrile AcOEt/EtOAc Ethylacetate AcOH acetic acid aq aqueous Ar aryl Bn benzyl Bu butyl (nBu =n-butyl, tBu = tert-butyl) CDI Carbonyldiimidazole CH₃CN AcetonitrileDBU 1,8-Diazabicyclo[5.4.0]-undec-7-ene Boc₂O di-tert-butyl dicarbonateDCE 1,2-Dichloroethane DCM Dichloromethane DiBAI-H DiisobutylaluminumHydride DIPEA N-Ethyldiisopropylamine DMAP Dimethylaminopyridine DMFN,N′-Dimethylformamide DMSO Dimethylsulfoxide El Electrospray ionisationEt₂O Diethylether Et₃N Triethylamine Ether Diethylether EtOAcEthylacetate EtOH Ethanol FC Flash Chromatography h hour(s) HATUO-(7-Azabenzotriazole-1-yl)-N,N,N′N′- tetramethyluroniumhexafluorophosphate HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HCI Hydrochloric acid HMPAHexamethylphosphoramide HOBt 1-Hydroxybenzotriazole HPLC HighPerformance Liquid Chromatography H₂O Water L liter(s) LC-MS LiquidChromatography Mass Spectrometry LiHMDS Lithium bis(trimethylsilyl)amideMgSO₄ Magnesium Sulfate Me methyl Mel Iodomethane MeOH Methanol mgmilligram min minute(s) mL milliliter MS Mass Spectrometry NaHCO₃ SodiumBicarbonate Na₂SO₄ Sodium Sulfate NH₂OH hydroxylamine Pd/C palladium oncharcoal Pd(OH)₂ palladium hydroxide PG protecting group Ph phenyl Ph₃Ptriphenyl phosphine Prep Preparative Rf ratio of fronts RP reverse phaseRt Retention time rt Room temperature SiO₂ Silica gel SOCl₂ ThionylChloride TBAF Tetrabutylammonium fluoride TEA Triethylamine TFATrifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer ChromatographyGeneral Conditions:

Mass spectra were run on LC-MS systems using electrospray ionization anda WATERS Acquity Single Quard Detector. [M+H]⁺ refers to mono-isotopicmolecular weights.

NMR spectra were run on open access Varian 400 NMR spectrometers.Spectra were measured at 298K and were referenced using the solventpeak.

If not indicated otherwise, the analytical UPLC conditions are asfollows:

Method A Column Phenonemax Kinetix C18 Column; 2.1 mm × 50 mm; 2.6 ucore size Column Temperature 50 ° C. Eluents solvent A: water with 0.1%TFA; solvent B: CH₃CN with 0.1% TFA Flow Rate 1.2 mL/min Gradient 2-88%solvent B in 9.5 mins

Example 1. Synthesis of3-(3-(4-bromophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[1-A, 1-B]

Reagents:

Step 1: NH₂OH.HCl, NaOH, water, 70° C. Step 2: NaH (60%),N,N-dimethylformamide, 0° C. to room temperature. Step 3: Et₂Zn,(R,R)-DIPT, tBuOCl, chloroform,1,4-dioxane, 0° C. to room temperature, 3h. Step 4: LiOH.H₂O, MeOH, water, room temperature. Step 5: NH₂O-THP,EDC.HCl, HOBT, TEA, dichloromethane, room temperature. Step 6: 35.5% aq.HCl, EtOH, room temperature.

Step 1. Synthesis of 4-bromobenzaldehyde oxime [1a]

4-Bromobenzaldehyde (5 g, 27.0 mmol, 1.0 equiv) was mixed with water (40ml) and the reaction mixture was stirred at 70° C. A solution ofhydroxylamine hydrochloride (2.27 g, 32.0 mmol, 1.2 equiv) and sodiumhydroxide (1.29 g, 35.0 mmol, 1.3 equiv) in water (10 mL) was added tothe reaction mixture at same temperature. The reaction mixture wasallowed to stir for 3 hours. The white precipitate was then filtered anddried to afford product 1a (5 g, 92% yield). ¹H NMR (400 MHz, DMSO) δ11.39 (s, 1H), 8.14 (s, 1H), 7.63-7.58 (m, 2H), 7.57-7.52 (m, 2H).

Step 2. Synthesis of ethyl 2-methyl-2-(methylsulfonyl)pent-4-enoate [1b]

Ethyl 2-(methylsulfonyl)propanoate (1 g, 5.6 mmol, 1.0 equiv) wasdissolved in N,N-dimethylformamide (7 mL) and cooled to 0° C. NaH (0.3g, 60% in mineral oil, 8.3 mmol, 1.5 equiv) was added. The reactionmixture was stirred at 0° C. for 1 hr. Allyl bromide (0.73 g, 6.1 mmol,1.1 equiv) was added to reaction mixture and the resulting mixture wasstirred at room temperature for 5 hours. The reaction mixture was thenquenched with water and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated. The crudeproduct was purified by silica gel column chromatography (0-30% EtOAc inHexane) to afford product 1b (0.7 g, 61.4% yield). LCMS (m/z): 238.2[M+18]. ¹H NMR (400 MHz, DMSO) δ 5.75-5.60 (m, 1H), 5.28-5.16 (m, 2H),4.27-4.16 (m, 2H), 3.14 (d, J=1.1 Hz, 3H), 2.97 (dd, J=13.4, 6.8 Hz,1H), 2.50-2.45 (m, 1H), 1.45 (d, J=3.8 Hz, 3H), 1.26-1.19 (m, 3H).

Step 3. Synthesis of Ethyl3-(3-(4-bromophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[1d-A & 1d-B]

1b (0.7 g, 3.4 mmol, 1.0 equiv) was dissolved in chloroform (10 ml) andcooled to 0° C. Diethyl zinc (1M in hexane) (0.94 g, 7.5 mmol, 2.2equiv) was added and the reaction mixture was stirred 0° C. for 10minutes. (R,R)-DIPT (0.79 g, 3.4 mmol, 1.0 equiv) was added and thereaction mixture was stirred at 0° C. for 1 hour. 1a (0.61 g, 3.1 mmol,1.0 equiv), 1,4-dioxane (0.73 g, 6.8 mmol, 2.0 equiv) and t-BuOCl (0.45g, 5.1 mmol, 1.5 equiv) were added. The reaction mixture was stirred atroom temperature for 3 hours. The reaction mixture was quenched withsaturated aqueous ammonium chloride solution and extracted with EtOAc.The organic layer was washed with brine, dried over sodium sulfate andconcentrated. The crude product was purified by silica gel columnchromatography (0-30% EtOAc in Hexane) to afford product 1d (0.55 g,37.0% yield). The product was further purified by preparative HPLCpurification to afford two diastereomers. 1d-A (0.2 g, 14.08%) LCMS(m/z): 418.2 [M−H]. 1d-B (0.19 g, 13.4%). LCMS (m/z): 418.2 [M−H]. ¹HNMR (400 MHz, DMSO) δ 7.72-7.65 (m, 2H), 7.64-7.58 (m, 2H), 5.01-4.87(m, 1H), 4.27-4.11 (m, 2H), 3.57 (dd, J=17.0, 10.2 Hz, 1H), 3.25-3.12(m, 1H), 2.63 (dd, J=13.8, 10.6 Hz, 1H), 2.06 (dd, J=13.9, 3.4 Hz, 1H),1.58 (s, 3H), 1.28-1.16 (m, 3H).

Step 4. Synthesis of3-(3-(4-bromophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [1e-A]

1d-A (0.2 g, 0.5 mmol, 1.0 equiv) was dissolved in MeOH (5 ml) and water(2 ml). LiOH.H₂O (0.04 g, 1.0 mmol, 2.0 equiv) was added and thereaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was diluted with water, acidified by 1N HCl aqueoussolution to the pH 3 to 4 and extracted with EtOAc. The organic layerwas washed with brine, dried over sodium sulfate and concentrated toafford product 1e (0.18 g, 96.5% yield). LCMS (m/z): 390.2 [M−H]. ¹H NMR(400 MHz, DMSO) δ 13.58 (s, 1H), 7.73-7.65 (m, 2H), 7.64-7.55 (m, 2H),4.96-4.87 (m, 1H), 3.58 (dd, J=17.0, 10.3 Hz, 1H), 3.19 (dd, J=17.1, 6.6Hz, 1H), 3.09 (s, 3H), 2.62 (dd, J=13.9, 10.0 Hz, 1H), 2.08 (dd, J=13.9,3.7 Hz, 1H), 1.54 (s, 3H).

Step 5. Synthesis of3-(3-(4-bromophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[1f-A]

1e-A (0.18 g, 0.5 mmol, 1.0 equiv) was dissolved in dichloromethane (3mL). TEA (0.23 g, 2.3 mmol, 5.0 equiv), EDC.HCl (0.13 g, 0.7 mmol, 1.5equiv), HOBT (0.11 g, 0.8 mmol, 1.8 equiv) andO-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.11 g, 0.9 mmol, 2.0 equiv)were added. The reaction mixture was stirred at room temperature for 20hours. The reaction mixture was concentrated under reduced pressure andthe residue was purified by silica gel column chromatography (0-5% MeOHin dichloromethane) to afford product 1f-A (0.2 g, 88.4% yield). LCMS(m/z): 489.4 [M−H]. ¹H NMR (400 MHz, DMSO) δ 11.32 (d, J=21.4 Hz, 1H),7.68 (d, J=8.6 Hz, 2H), 7.60 (dd, J=8.6, 1.2 Hz, 2H), 4.88-4.77 (m, 1H),4.57 (d, J=4.9 Hz, 1H), 4.01 (d, J=12.0 Hz, 1H), 3.82-3.70 (m, 1H),3.63-3.47 (m, 2H), 3.47-3.39 (m, 1H), 3.17 (ddd, J=17.0, 7.5, 4.5 Hz,1H), 3.04 (d, J=5.6 Hz, 3H), 2.71 (td, J=12.9, 9.1 Hz, 1H), 2.13-1.99(m, 1H), 1.65-1.60 (m, 1H), 1.58 (s, 3H), 1.53 (dd, J=15.2, 7.5 Hz, 3H),1.49-1.42 (m, 3H).

Step 6. Synthesis of3-(3-(4-bromophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[1-A]

1f-A (0.065 g, 1.0 mmol, 1.0 equiv) was dissolved in ethanol (1 mL).35.5% aq. HCl (1 mL) was added and the reaction mixture was stirred atroom temperature for 3 hours. The reaction mixture was concentratedunder reduced pressure to afford a residue. The residue was trituratedwith n-pentane, solvent was decanted. The reaming material product wasfurther purified by preparative HPLC purification to afford product 1-A(0.026 g, 48.4% yield). LCMS (m/z): 405.2 [M−H]. ¹H NMR (400 MHz, DMSO)δ 10.87 (s, 1H), 9.15 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6Hz, 2H), 4.78 (dd, J=20.6, 10.7 Hz, 1H), 3.58 (dd, J=17.0, 10.3 Hz, 1H),3.16 (dd, J=17.0, 7.9 Hz, 1H), 2.74 (dd, J=13.8, 8.5 Hz, 1H), 2.07 (dd,J=13.8, 4.4 Hz, 1H), 1.58 (d, J=13.7 Hz, 3H).

The diastereomer3-(3-(4-bromophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[1-B] was synthesized from 1d-B following the procedures described inStep 4-6. LCMS (m/z): 405.2 [M−H]. ¹H NMR (400 MHz, DMSO) δ 11.06 (s,1H), 9.29 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 4.65(td, J=11.5, 3.5 Hz, 1H), 3.57 (dt, J=26.4, 13.2 Hz, 1H), 3.14 (dd,J=17.1, 8.1 Hz, 1H), 3.10-3.00 (m, 3H), 2.66 (dd, J=14.0, 3.3 Hz, 1H),2.12-1.99 (m, 1H), 1.59 (s, 3H).

Example 2. Synthesis of compound(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[2-A]

Reagents:

Step 1: NCS, DMF, 50° C. Step 2: TEA, diethyl ether, 0° C. to roomtemperature. Step 3: DBU, dppb, PdCl₂(PPh₃)₂, DMSO, 100° C. Step 4:LiOH.H₂O, THF, MeOH, water, room temperature. Step 5: NH₂OTHP, EDC.HCl,HOBT, N-methyl morpholine, THF, room temperature. Step 6: HCl (in IPA),MeOH, dichloromethane, room temperature.

Step 1. Synthesis of 4-bromo-N-hydroxybenzimidoyl chloride [1a]

Bromobenzaldehyde oxime (2 g, 10.0 mmol, 1.0 equiv) was dissolved in DMF(20 mL). NCS (2 g, 15.0 mmol, 1.5 equiv) was added and the reactionmixture was stirred at 50° C. for 2 hours. The reaction was quenchedwith water and extracted with EtOAc. The organic layer was washed withbrine, dried over sodium sulfate and concentrated to afford a cruderesidue. The crude residue was purified by silica gel columnchromatography (10% Hexane) to afford the desired product 1a (2 g, 85%yield). ¹H NMR (400 MHz, DMSO) δ 12.56 (s, 1H), 7.78-7.64 (m, 4H).

Step 2. Synthesis of (R)-ethyl3-((R)-3-(4-bromophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[1d-A]

Racemic material 1b was separated into two enantiomers by chiral HPLCwith following conditions. Instrumentation: VWR La Prep. HPLC system;

Mobile phase: Heptane/Ethanol 95/5;

Flow rate: 170 mL/min;

Column: Chiralpak AD 20 uM 7.65×39.3 cm+5×50 cm;

Detection UV: 210 nM.

The second fraction was determined to be (R)-ethyl2-methyl-2-(methylsulfonyl)pent-4-enoate (R)-1b.

A flask was charged with 1a (2.04 g, 10.2 mmol, 1.5 equiv), (R)-1d-A(1.5 g, 6.8 mmol, 1.0 equiv) and diethyl ether (25 mL). At 0° C., TEA(1.37 g, 13.6 mmol, 2.0 equiv) was added and the reaction mixture wasstirred at room temperature for 3 hours. The reaction mixture wasquenched with water and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated. The cruderesidue was purified by silica gel column chromatography (column packedin 50% dichloromethane/Hexane, eluent system-1 to 47% EtOAc) to affordtwo diastereomers (R)-1d-A and (R)-1d-B. (R)-1d-A: (1 g, 35.1% yield).LCMS (m/z): 418.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.68 (d, J=8.6 Hz,2H), 7.61 (d, J=8.6 Hz, 2H), 4.83-4.71 (m, 1H), 4.26 (q, J=7.1 Hz, 2H),3.62 (dd, J=17.0, 10.4 Hz, 1H), 3.23-3.15 (m, 1H), 3.15 (d, J=7.1 Hz,3H), 2.60 (dd, J=14.5, 3.3 Hz, 1H), 2.19 (dd, J=14.5, 8.5 Hz, 1H), 1.63(s, 3H), 1.26 (t, J=7.1 Hz, 3H). (R)-1d-B: (0.8 g, 28% yield). LCMS(m/z): 418.1 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.68 (d, J=8.6 Hz, 2H),7.61 (d, J=8.6 Hz, 2H), 4.98-4.89 (m, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.57(dd, J=17.0, 10.2 Hz, 1H), 3.22-3.15 (m, 1H), 3.11 (d, J=13.6 Hz, 3H),2.63 (dd, J=13.9, 10.7 Hz, 1H), 2.06 (dd, J=13.8, 3.3 Hz, 1H), 1.55 (d,J=20.4 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H). The less polar diastereomer,structure shown as (R)-1d-Awas used in the following step.

Step 3. Synthesis of ethyl(2R)-2-methyl-2-(methylsulfonyl)-3-(3-(4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanoate[2b]

A flask was charged with (R)-1d-A (1 g, 2.39 mmol, 1.0 equiv) and DMSO(10 mL). But-2-ynoic acid (0.3 g, 3.58 mmol, 1.5 equiv), 1,4-Bis(diphenylphosphino) butane (0.023 g, 0.05 mmol, 0.02 equiv), DBU (0.73g, 4.78 mmol, 2.0 equiv) were added and the reaction mixture wasdegassed for 10 minutes. PdCl₂(PPh₃)₂ (0.018 g, 0.026 mmol, 0.01 equiv)was added and the reaction mixture was stirred at 100° C. for 3 hours.The reaction mixture was quenched with water and extracted with EtOAc.The organic layer was washed with brine, dried over sodium sulfate andconcentrated. The crude residue was purified by silica gel columnchromatography (35-40% EtOAc/Hexane) to afford product 2b (0.8 g, 88%yield). LCMS (m/z): 378.2 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.62 (d, J=8.4Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 4.76 (ddd, J=11.3, 8.3, 3.4 Hz, 1H),4.27 (q, J=7.1 Hz, 2H), 3.61 (dd, J=17.0, 10.3 Hz, 1H), 3.22-3.06 (m,4H), 2.59 (dd, J=14.4, 3.3 Hz, 1H), 2.19 (dd, J=14.4, 8.5 Hz, 1H), 2.07(s, 3H), 1.63 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).

Step 4. Synthesis of(R)-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanoicacid [2c]

2b (0.8 g, 2.12 mmol, 1.0 equiv) was dissolved in THF (16 mL), MeOH (2mL) and water (2 mL). LiOH.H₂O (0.17 g, 4.24 mmol, 2.0 equiv) was addedand the reaction mixture was stirred at room temperature for 2 hours.The reaction mixture was acidified by 1.0 N HCl aqueous solution up topH 4 to 5 and extracted with EtOAc. The organic layer was washed withbrine, dried over sodium sulfate and concentrated to afford product 2c(0.62 g, 84% yield). The product was directly used in the next step withno further purification. LCMS (m/z): 350.1 [M+H]. ¹H NMR (400 MHz, DMSO)δ 14.03 (s, 1H), 7.70-7.58 (m, 2H), 7.46 (d, J=8.3 Hz, 2H), 4.77 (dd,J=15.6, 7.8 Hz, 1H), 3.62 (dd, J=17.0, 10.4 Hz, 1H), 3.24-3.15 (m, 1H),3.16-3.07 (m, 3H), 2.56 (d, J=3.1 Hz, 1H), 2.15 (dd, J=14.3, 8.5 Hz,1H), 2.07 (s, 3H), 1.60 (s, 3H).

Step 5. Synthesis of(2R)-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[2d]

A flask was charged with 2c (0.6 g, 1.7 mmol, 1.0 equiv) and THF (25mL). N-methyl morpholine (0.87 g, 8.6 mmol, 5.0 equiv), HOBT (0.28 g,2.0 mmol, 1.2 equiv), 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.4 g,3.4 mmol, 2.0 equiv), EDC.HCl (0.49 g, 2.6 mmol, 1.5 equiv) were addedand the reaction mixture was stirred at room temperature for 24 hours.The reaction mixture was quenched with water and extracted with EtOAc.The organic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (35-50% EtOAc/Hexane) to afford product 2d (0.65 g, 88%yield). LCMS (m/z): 365.0 [M-THP]. ¹H NMR (400 MHz, DMSO) δ 11.47 (s,1H), 7.61 (dd, J=8.4, 1.7 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 4.97 (d,J=8.6 Hz, 1H), 4.67 (d, J=9.8 Hz, 1H), 4.07 (dd, J=18.4, 10.0 Hz, 1H),3.64-3.43 (m, 2H), 3.14 (dd, J=17.1, 7.5 Hz, 1H), 3.06 (d, J=8.7 Hz,3H), 2.71-2.63 (m, 1H), 2.06 (d, J=6.7 Hz, 3H), 1.70 (s, 3H), 1.61 (d,J=4.3 Hz, 3H), 1.54 (s, 3H).

Step 6. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[2-A]

2d (0.6 g, 1.33 mmol, 1.0 equiv) was dissolved in methanol (4 mL) anddichloromethane (4 mL). 10% HCl (in IPA) (0.3 mL) was added and thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was quenched with water, neutralized by saturatedaqueous sodium bicarbonate solution and extracted with EtOAc. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was triturated with n-pentane/diethyl ether,solvent was decanted and dried to afford product 2-A (0.48 g, 90%yield). LCMS (m/z): 365.1 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.06 (s, 1H),9.28 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 4.63 (dt,J=11.6, 5.9 Hz, 1H), 3.57 (dd, J=17.0, 10.4 Hz, 1H), 3.14 (dd, J=17.1,8.1 Hz, 1H), 3.05 (d, J=11.5 Hz, 3H), 2.66 (dd, J=14.2, 3.3 Hz, 1H),2.07 (s, 3H), 2.02 (dd, J=14.6, 6.2 Hz, 1H), 1.59 (s, 3H).

Example 3. Synthesis of3-(3-([1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[3-A, 3-B]

Reagents:

Step 1: CH₃COOK, PdCl₂ (dppf), 1,4-dioxane, 100° C. Step 2: LiOH.H₂O,MeOH, water, room temperature. Step 3: NH₂O-THP, EDC.HCl, HOBT, TEA,dichloromethane, room temperature. Step 4: 35.5% aq. HCl, EtOH, roomtemperature.

Step 1. Synthesis of ethyl3-(3-([1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[3a]

1d-A & 1-d-B (0.5 g, 1.0 mmol, 1.0 equiv), phenylboronic acid (0.18 g,1.2 mmol, 1.2 equiv) and potassium acetate (0.351 g, 2.9 mmol, 3.0equiv) were dissolved in 1, 4-dioxane (10 mL) and degassed for 5minutes. PdCl₂(dppf) (0.087 g, 0.1 mmol, 0.1 equiv) was added to thereaction mixture. The resulting reaction mixture was stirred at 100° C.for 4 hours. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (0-50% EtOAc in Hexane) to afford product 3a (0.35 g,70.6% yield). LCMS (m/z): 416 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.75 (dt,J=8.6, 7.5 Hz, 6H), 7.49 (t, J=7.5 Hz, 2H), 7.40 (t, J=7.4 Hz, 1H),5.01-4.87 (m, 1H), 4.35-4.15 (m, 2H), 3.64 (dd, J=17.7, 11.2 Hz, 1H),3.29-3.16 (m, 1H), 3.11 (d, J=21.0 Hz, 3H), 2.63 (t, J=12.4 Hz, 1H),2.19 (dd, J=14.5, 8.5 Hz, 1H), 2.07 (d, J=13.3 Hz, 1H), 1.68-1.53 (m,3H), 1.26-1.18 (m, 3H).

Step 3. Synthesis of3-(3-([1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [3b]

3a (0.35 g, 0.8 mmol, 1.0 equiv) was dissolved in MeOH (4 mL) and water(2 mL). LiOH.H₂O (0.070 g, 1.6 mmol, 2.0 equiv) was added and thereaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was diluted with water, acidified by 1N HCl aqueoussolution to the pH 3 to 4 and extracted with EtOAc. The organic layerwas washed with brine, dried over sodium sulfate and concentrated toafford product 3b (0.24 g, 73.6% yield). The product was used in thenext step without further purification. LCMS (m/z): 388.1 [M+H]. ¹H NMR(400 MHz, DMSO) δ 13.62 (s, 1H), 7.85-7.69 (m, 6H), 7.50 (t, J=7.6 Hz,2H), 7.45-7.38 (m, 1H), 5.02-4.70 (m, 1H), 3.76-3.57 (m, 1H), 3.23 (ddd,J=16.9, 7.3, 4.3 Hz, 1H), 3.17-3.03 (m, 3H), 2.61 (ddd, J=17.6, 13.9,6.6 Hz, 1H), 2.14 (ddd, J=17.5, 14.0, 6.0 Hz, 1H), 1.59 (d, J=21.1 Hz,3H).

Step 4. Synthesis of3-(3-([1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[3c]

3b (0.24 g, 0.6 mmol, 1.0 equiv) was dissolved in dichloromethane (5mL). TEA (0.31 g, 3.0 mmol, 5.0 equiv) was added. EDC.HCl (0.18 g, 0.9mmol, 1.5 equiv), HOBt (0.15 g, 1.1 mmol, 1.8 equiv) andO-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.145 g, 1.2 mmol, 2.0equiv) were added. The reaction mixture was stirred at room temperaturefor 20 hours. The reaction mixture was concentrated under reducedpressure to afford a crude product. The crude product was purified bysilica gel column chromatography (0-4% MeOH in dichloromethane) toafford product 3c (0.2 g, 66.4% yield). LCMS (m/z): 487.4 [M+H]. ¹H NMR(400 MHz, DMSO) δ 7.76 (dt, J=8.6, 7.9 Hz, 6H), 7.50 (t, J=7.6 Hz, 2H),7.41 (t, J=7.3 Hz, 1H), 4.86-4.65 (m, 1H), 4.05 (dd, J=28.6, 21.5 Hz,1H), 3.77 (ddd, J=11.1, 7.9, 3.1 Hz, 1H), 3.62 (ddd, J=21.0, 10.3, 5.1Hz, 1H), 3.47-3.39 (m, 2H), 3.27-3.15 (m, 1H), 3.07 (t, J=7.2 Hz, 3H),2.79-2.65 (m, 1H), 2.10 (ddd, J=16.7, 9.9, 5.0 Hz, 1H), 1.65-1.52 (m,6H).

Step 5. Synthesis of3-(3-([1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[3-A, 3-B]

3c (0.2 g, 0.4 mmol, 1.0 equiv) was dissolved in ethanol (2 ml). 35.5%aq. HCl (1 mL) was added and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated underreduced pressure to dryness to obtain a residue. The crude product waspurified by preparative HPLC purification to afford product 3 as twodiastereomers (3-A (0.027 g, 16.3% yield), LCMS (m/z): 403.2[M+H]. ¹HNMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.17 (s, 1H), 7.75 (dt, J=7.2, 6.6Hz, 6H), 7.50 (t, J=7.6 Hz, 2H), 7.41 (t, J=7.3 Hz, 1H), 4.80 (d, J=9.9Hz, 1H), 3.63 (dd, J=16.9, 10.3 Hz, 1H), 3.21 (dd, J=17.0, 8.0 Hz, 1H),3.07 (s, 3H), 2.76 (dd, J=13.9, 8.6 Hz, 1H), 2.09 (dd, J=13.9, 4.5 Hz,1H), 1.58 (s, 3H). 3-B (0.023 g, 13.9% yield), LCMS (m/z): 403.2 [M+H].¹H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.31 (s, 1H), 7.85-7.70 (m, 6H),7.50 (t, J=7.5 Hz, 2H), 7.41 (t, J=7.3 Hz, 1H), 4.66 (d, J=7.0 Hz, 1H),3.62 (dd, J=16.9, 10.3 Hz, 1H), 3.19 (dd, J=17.0, 8.0 Hz, 1H), 3.07 (d,J=5.9 Hz, 3H), 2.69 (dd, J=14.0, 3.5 Hz, 1H), 2.07 (dd, J=14.0, 8.5 Hz,1H), 1.61 (s, 3H).

Example 4. Synthesis of3-(3-(4-(but-2-yn-1-yloxy)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[4-A, 4-B]

Reagents: Step 1: Triphenylphosphine, DEAD, benzene, THF, roomtemperature. Step 2: NH₂OH.HCl, NaOH, water, 70° C. Step 3: Et₂Zn,(R,R)-DIPT, t-BuOCl, chloroform, 1,4-dioxane, 0° C. to room temperature,4 h. Step 4: LiOH.H₂O, MeOH, water, room temperature. Step 5: NH₂OTHP,EDC.HCl, HOBT, TEA, dichloromethane, room temperature. Step 6: 35.5% aq.HCl, EtOH, room temperature.

Step 1. Synthesis of 4-(but-2-yn-1-yloxy)benzaldehyde [4a]

But-2-yn-1-ol (2.58 g, 36.9 mmol, 1.5 equiv), triphenylphosphine (7.73g, 29.5 mmol, 1.2 equiv) and 4-hydroxybenzaldehyde (3 g, 24.6 mmol, 1.0equiv) were mixed with benzene:THF (2:1, 30 mL). The reaction mixturewas stirred at room temperature for 10 minutes. DEAD (5.13 g, 29.5 mmol,1.2 equiv) was added gradually and the reaction mixture was allowed tostir for 2 hours. The reaction mixture was quenched with water andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The residue was purified by silicagel column chromatography (0-25% EtOAc in Hexane) to afford product 4a(3.5 g, 81.8% yield). LCMS (m/z): 175.2 [M+H]. ¹H NMR (400 MHz, DMSO) δ9.92-9.84 (m, 1H), 7.95-7.83 (m, 2H), 7.24-7.10 (m, 2H), 4.89 (q, J=2.3Hz, 2H), 1.88-1.81 (m, 3H).

Step 2. Synthesis of (E)-4-(but-2-yn-1-yloxy)benzaldehyde oxime [4b]

A mixture of 4a (3.5 g, 20.1 mmol, 1.0 equiv) and water (20 ml) wasstirred at 70° C. A solution of hydroxylamine hydrochloride (1.68 g,24.1 mmol, 1.2 equiv) and sodium hydroxide (1.04 g, 26.1 mmol, 1.3equiv) in water (10 mL) was added to the reaction mixture at sametemperature. The reaction mixture was allowed to stir at 70° C. for 3hours. The reaction mixture was cooled to 0° C. and the precipitate wascollected by filtration to afford product 4b (2.8 g, 73.2% yield). LCMS(m/z): 190.1 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.07 (s,1H), 7.53 (d, J=8.8 Hz, 2H), 7.00 (t, J=8.9 Hz, 2H), 4.78 (dq, J=4.5,2.3 Hz, 2H), 1.89-1.79 (m, 3H).

Step 3. Synthesis of ethyl3-(3-(4-(but-2-yn-1-yloxy)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[4c]

1b (1.25 g, 5.7 mmol, 1.0 equiv) was dissolved in chloroform (20 ml) andcooled to 0° C. Diethyl zinc (1.0 M in hexane) (1.57 g, 12.5 mmol, 2.2equiv) was added and the reaction mixture was stirred 0° C. for 10minutes. (R, R)-DIPT (1.33 g, 5.7 mmol, 1.0 equiv) was added and thereaction mixture was stirred at 0° C. for 7 hours. 4b (1.29 g, 6.8 mmol,1.0 equiv), 1,4-dioxane (0.75 g, 8.5 mmol, 1.5 equiv) and t-BuOCl (1.22g, 11.4 mmol, 2.0 equiv) were then added. The reaction mixture wasstirred at room temperature for 4 hours. The reaction mixture wasquenched with saturated aqueous ammonium chloride solution and extractedwith dichloromethane. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The crude product was purified bysilica gel column chromatography (0-60% EtOAc in Hexane) to affordproduct 4c (1.6 g, 69.2% yield). LCMS (m/z): 408.3 [M+H]. ¹H NMR (400MHz, DMSO) δ 7.67-7.48 (m, 2H), 7.06 (t, J=12.3 Hz, 2H), 4.93 (td,J=12.2, 6.0 Hz, 1H), 4.88-4.76 (m, 2H), 4.38-4.13 (m, 3H), 3.65-3.46 (m,1H), 3.23-3.04 (m, 4H), 2.68-2.55 (m, 1H), 2.10 (ddd, J=17.2, 14.1, 5.9Hz, 1H), 1.84 (t, J=2.1 Hz, 3H), 1.68-1.50 (m, 3H), 1.21 (ddt, J=16.0,9.7, 5.0 Hz, 3H).

Step 4. Synthesis of3-(3-(4-(but-2-yn-1-yloxy)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [4d]

4c (1.6 g, 3.9 mmol, 1.0 equiv) was dissolved in MeOH (10 ml) and water(8 ml). LiOH.H₂O (0.33 g, 7.8 mmol, 2.0 equiv) was added and thereaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was diluted with water, acidified by 1.0 N HCl aqueoussolution to the pH 3 and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated. The crudeproduct was triturated with n-pentane, the solvent was decanted toafford product 4d (1.05 g, 70.5% yield. LCMS (m/z): 380.1 [M+H]. ¹H NMR(400 MHz, DMSO) δ 13.78 (d, J=180.1 Hz, 1H), 7.72-7.38 (m, 2H),7.15-6.95 (m, 2H), 4.93-4.66 (m, 3H), 3.58 (ddd, J=20.6, 16.9, 10.2 Hz,1H), 3.23-2.94 (m, 4H), 2.69-2.52 (m, 1H), 2.09 (ddd, J=17.4, 14.0, 6.0Hz, 1H), 1.84 (t, J=2.1 Hz, 3H), 1.69-1.45 (m, 3H).

Step 5. Synthesis of3-((R)-3-(4-(but-2-yn-1-yloxy)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[4e]

4d (0.5 g, 1.3 mmol, 1.0 equiv) was dissolved in dichloromethane (10mL). TEA (0.66 g, 6.6 mmol, 5.0 equiv) was added. EDC.HCl (0.38 g, 2.0mmol, 1.5 equiv), HOBT (0.32 g, 2.4 mmol, 1.8 equiv) andO-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.31 g, 2.6 mmol, 2.0 equiv)were added. The reaction mixture was stirred at room temperature for 20hours. The reaction mixture was concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography (0-3%MeOH in dichloromethane) to afford product 4e (0.47 g, 74.5% yield).LCMS (m/z): 479.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.68-7.56 (m, 2H),7.04 (d, J=8.9 Hz, 2H), 4.70 (d, J=56.0 Hz, 1H), 4.07 (d, J=37.1 Hz,1H), 3.52 (ddd, J=15.1, 10.6, 6.2 Hz, 2H), 3.20-2.97 (m, 4H), 2.75-2.61(m, 1H), 2.12-1.95 (m, 1H), 1.56 (d, J=16.6 Hz, 6H).

Step 6. Synthesis of3-(3-(4-(but-2-yn-1-yloxy)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[4-A, 4-B]

4e (0.47 g, 0.9 mmol, 1.0 equiv) was dissolved in ethanol (5 ml). 35.5%aq. HCl (2 mL) was added and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated underreduced pressure. The crude product was purified by preparative HPLCpurification to afford product 4 as two diastereomers (4-A (0.055 g,14.5% yield), LCMS (m/z): 395.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ 10.86(s, 1H), 9.15 (s, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.04 (d, J=8.3 Hz, 2H),4.80 (s, 2H), 4.72 (s, 1H), 3.55 (dd, J=17.0, 10.3 Hz, 1H), 3.13 (dd,J=16.8, 7.9 Hz, 1H), 3.05 (s, 3H), 2.76-2.67 (m, 1H), 2.05 (d, J=14.1Hz, 1H), 1.84 (s, 3H), 1.56 (s, 3H). 4-B (0.050 g, 13.2% yield) LCMS(m/z): 395.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 9.28 (s,1H), 7.60 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 4.81 (s, 2H), 4.59(d, J=7.5 Hz, 1H), 3.55 (dd, J=17.1, 10.5 Hz, 1H), 3.19-3.09 (m, 1H),3.07 (s, 3H), 2.65 (d, J=17.1 Hz, 1H), 2.02 (dd, J=14.2, 8.4 Hz, 1H),1.84 (s, 3H), 1.59 (s, 3H).

Example 5. Synthesis of compounds3-(3-(4-cyclopropylphenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[5-A, 5-B]

Reagents:

Step 1: Pd(OAc)₂, tricyclohexyl phosphine, K₃PO₄, 1,4-dioxane, Water,130° C. Step 2: LiOH.H₂O, THF, MeOH, water, room temperature. Step 3:NH₂O-THP, EDC.HCl, HOBT, TEA, dichloromethane, room temperature. Step 4:35.5% aq. HCl, EtOH, room temperature.

Step 1. Synthesis of ethyl3-(3-(4-cyclopropylphenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[5a]

1d-A & 1d-B (0.25 g, 0.6 mmol, 1.0 equiv), cyclopropylboronic acid(0.062 g, 0.7 mmol, 1.2 equiv), K₃PO₄ (0.38 g, 1.8 mmol, 3.0 equiv) andtricyclohexyl phosphine (0.017 g, 0.06 mmol, 0.1 equiv) were dissolvedin 1,4-dioxane:water (4:1, 15 mL) and degassed for 10 minutes. Pd(OAc)₂(0.007 g, 0.02 mmol, 0.05 equiv) was added and the resulting reactionmixture was stirred at 130° C. for 1 hour. The reaction mixture wasquenched with water and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated. The crudeproduct was purified by silica gel column chromatography (20-30% EtOAcin Hexane) to afford product 5a (0.19 g, 64.2% yield). LCMS (m/z): 380.2[M+H]. ¹H NMR (400 MHz, DMSO) δ 7.65 (d, J=20.3 Hz, 2H), 7.56-7.44 (m,2H), 4.89 (d, J=27.7 Hz, 1H), 4.34-4.12 (m, 2H), 3.58 (dd, J=17.5, 10.5Hz, 1H), 3.16 (ddd, J=32.2, 19.0, 4.3 Hz, 4H), 2.71-2.55 (m, 1H),2.26-2.11 (m, 1H), 2.08 (s, 1H), 1.61 (dd, J=22.2, 3.7 Hz, 3H),1.25-1.21 (m, 3H), 1.05-0.69 (m, 4H).

Step 2. Synthesis of3-(3-(4-cyclopropylphenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [5b]

5a (0.19 g, 0.5 mmol, 1.0 equiv) was dissolved in THF (4 mL), MeOH (1mL) and water (1 mL). LiOH.H₂O (0.063 g, 1.5 mmol, 3.0 equiv) was addedand the reaction mixture was stirred at room temperature for 3 hours.The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with water, acidified by 1.0 N HCl aqueous solutionto the pH 3 and extracted with EtOAc. The organic layer was washed withbrine, dried over sodium sulfate and concentrated to afford product 5b(0.155 g, 88.1% yield). LCMS (m/z): 352.3 [M+H]. ¹H NMR (400 MHz, DMSO)δ 7.67 (d, J=4.4 Hz, 2H), 7.55-7.43 (m, 2H), 4.89 (s, 1H), 3.59 (dd,J=18.3, 11.3 Hz, 1H), 3.20 (d, J=13.9 Hz, 1H), 3.11 (dd, J=16.9, 2.1 Hz,3H), 2.64 (d, J=32.5 Hz, 1H), 2.27-2.02 (m, 2H), 1.57 (dd, J=20.8, 3.8Hz, 3H), 1.20-0.99 (m, 2H), 0.90-0.69 (m, 2H).

Step 3. Synthesis of3-(3-(4-cyclopropylphenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[5c]

5b (0.155 g, 0.4 mmol, 1.0 equiv) was dissolved in dichloromethane (5mL). TEA (0.22 g, 2.22 mmol, 5.0 equiv) was added. EDC.HCl (0.13 g, 0.7mmol, 1.5 equiv), HOBT (0.107 g, 0.8 mmol, 1.8 equiv) andO-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.103 g, 0.9 mmol, 2.0equiv) were added. The reaction mixture was stirred at room temperaturefor 24 hours. The reaction mixture was concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography (0.5-2% MeOH in dichloromethane) to afford product 5c(0.145 g, 72.5% yield). LCMS (m/z): 454.3 [M+18]. ¹H NMR (400 MHz, DMSO)δ 7.67 (d, J=4.4 Hz, 2H), 7.55-7.43 (m, 2H), 4.89 (s, 1H), 3.59 (dd,J=18.3, 11.3 Hz, 1H), 3.20 (d, J=13.9 Hz, 1H), 3.11 (dd, J=16.9, 2.1 Hz,3H), 2.64 (d, J=32.5 Hz, 1H), 2.27-2.02 (m, 2H), 1.57 (dd, J=20.8, 3.8Hz, 3H), 1.20-0.99 (m, 2H), 0.90-0.69 (m, 2H).

Step 4. Synthesis of3-(3-(4-cyclopropylphenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[5-A, 5-B]

5c (0.145 g, 0.3 mmol, 1.0 equiv) was dissolved in ethanol (2 ml). 35.5%aq. HCl (0.5 mL) was added and the reaction mixture was stirred at roomtemperature for 6 hours. The reaction mixture was concentrated underreduced pressure to dryness. The crude product was purified bypreparative HPLC purification to afford product 5 as two diastereomers.5-A: 0.020 g, 17.1% yield, LCMS (m/z): 367.2 [M+H]. ¹H NMR (400 MHz,DMSO) δ 10.86 (s, 1H), 9.15 (s, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.15 (d,J=8.4 Hz, 2H), 4.72 (s, 1H), 3.55 (dd, J=16.9, 10.2 Hz, 2H), 3.15 (d,J=8.1 Hz, 1H), 3.05 (s, 3H), 2.74 (d, J=8.8 Hz, 1H), 2.07 (dd, J=10.3,6.0 Hz, 1H), 1.98-1.92 (m, 1H), 1.55 (s, 3H), 1.00 (dt, J=6.2, 4.2 Hz,2H), 0.72 (dt, J=6.5, 4.3 Hz, 2H). 5-B (0.015 g, 12.8% yield), LCMS(m/z): 367.2 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 9.29 (s,1H), 7.52 (d, J=8.3 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 4.60 (s, 1H), 3.54(dd, J=16.9, 10.3 Hz, 1H), 3.16-3.08 (m, 1H), 3.07 (s, 3H), 2.64 (s,1H), 2.07-1.92 (m, 2H), 1.59 (s, 3H), 1.00 (dt, J=6.3, 4.2 Hz, 2H),0.75-0.65 (m, 2H).

Example 6. Synthesis of(R)-3-((R)-3-(4-(cyclopropylethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[6-A]

Reagents: Step 1: Diethyl amine, triphenyl phosphine, CuI, PdCl₂(pph₃)₂,DMF, 100° C. Step 2: LiOH.H₂O, THF, MeOH, water, room temperature. Step3: NH₂OTHP, EDC.HCl, HOBT, N-methyl morpholine, THF, room temperature.Step 4: HCl (in IPA), MeOH, dichloromethane, room temperature.

Step 1. Synthesis of (R)-ethyl3-((R)-3-(4-(cyclopropylethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[6a]

A flask was charged with (R)-1d-A (0.75 g, 1.79 mmol, 1.0 equiv),diethyl amine (10 mL) and DMF (2 mL). CuI (0.017 g, 0.089 mmol, 0.05equiv), triphenyl phosphine (0.093 g, 0.36 mmol, 0.2 equiv) were addedand the reaction mixture was degassed for 10 minutes. PdC₂(pph₃)₂ (0.062g, 0.089 mmol, 0.05 equiv), ethynylcyclopropane (0.24 g, 3.58 mmol, 2.0equiv) were added and the reaction mixture was stirred at 100° C. for 4hours. The reaction mixture was quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (25-40% EtOAc/Hexane) to afford product 6a (0.6 g, 83%yield). LCMS (m/z): 404.2 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.61 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 4.75 (d, J=7.5 Hz, 1H), 4.26 (q, J=7.1Hz, 2H), 3.60 (dd, J=17.0, 10.3 Hz, 1H), 3.20-3.11 (m, 4H), 2.61 (s,1H), 2.21-2.16 (m, 1H), 1.63 (s, 3H), 1.60-1.55 (m, 1H), 1.25 (t, J=7.1Hz, 3H), 0.95-0.88 (m, 2H), 0.76 (dt, J=6.9, 3.9 Hz, 2H).

Step 2. Synthesis of(R)-3-((R)-3-(4-(cyclopropylethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [6b]

6a (0.6 g, 1.49 mmol, 1.0 equiv) was dissolved in THF (12 mL), MeOH (3mL) and water (3 mL). LiOH.H₂O (0.13 g, 2.97 mmol, 2.0 equiv) was addedand the reaction mixture was stirred at room temperature for 2 hours.The reaction mixture was poured to water, neutralized by 2.0 N HClaqueous solution and extracted with EtOAc. The organic layer was washedwith brine, dried over sodium sulfate and concentrated to afford product6b (0.5 g, 90% yield). LCMS (m/z): 376.2 [M+H]. The product was directlyused in the next step with no further purification. ¹H NMR (400 MHz,DMSO) δ 14.02 (s, 1H), 7.60 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H),4.76 (d, J=7.8 Hz, 1H), 3.61 (dd, J=16.9, 10.3 Hz, 1H), 3.25-2.99 (m,4H), 2.55 (s, 1H), 2.15 (dd, J=14.3, 8.4 Hz, 1H), 1.73-1.49 (m, 4H),0.98-0.85 (m, 2H), 0.83-0.64 (m, 2H).

Step 3. Synthesis of(2R)-3-((R)-3-(4-(cyclopropylethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[6c]

6b (0.5 g, 1.34 mmol, 1.0 equiv) was dissolved in THF (35 mL). N-methylmorpholine (0.68 g, 6.68 mmol, 5.0 equiv), HOBT (0.22 g, 1.6 mmol, 1.2equiv), O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.32 g, 2.67 mmol,2.0 equiv) and EDC.HCl (0.38 g, 2.0 mmol, 1.5 equiv) were added and thereaction mixture was stirred at room temperature for 24 hours. Thereaction mixture was quenched with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (40-60% EtOAc/Hexane) to afford product 6c (0.55 g, 87%yield). LCMS (m/z): 475.5 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.47 (s, 1H),7.59 (dd, J=8.4, 1.7 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 4.97 (d, J=8.3 Hz,1H), 4.68 (s, 1H), 4.15-4.04 (m, 1H), 3.55 (ddd, J=33.2, 16.6, 7.8 Hz,2H), 3.14 (dd, J=17.1, 8.1 Hz, 1H), 3.06 (d, J=8.7 Hz, 3H), 2.66 (d,J=10.8 Hz, 1H), 2.06 (dd, J=13.7, 8.5 Hz, 1H), 1.69 (s, 3H), 1.64-1.38(m, 6H), 0.96-0.85 (m, 2H), 0.81-0.64 (m, 2H).

Step 4. Synthesis of(R)-3-((R)-3-(4-(cyclopropylethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[6-A]

6c (0.55 g, 1.16 mmol, 1.0 equiv) was dissolved in methanol (5 mL) anddichloromethane (5 mL). 10% HCl (in IPA) (0.25 mL) was added and thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was quenched with water, neutralized by saturatedaqueous sodium bicarbonate solution and extracted with EtOAc. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated to afford crude product. The crude product was trituratedwith n-pentane/diethyl ether to afford product 6-A (0.43 g, 94% yield).LCMS (m/z): 391.2 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 9.28(s, 1H), 7.62 (t, J=14.4 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 4.64 (d, J=7.4Hz, 1H), 3.56 (dd, J=17.0, 10.4 Hz, 1H), 3.18-3.11 (m, 1H), 3.06 (s,3H), 2.69-2.63 (m, 1H), 2.04 (dd, J=14.0, 8.5 Hz, 1H), 1.65-1.50 (m,4H), 0.96-0.87 (m, 2H), 0.80-0.69 (m, 2H).

Example 8. Synthesis of3-(3-(4-(but-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[8-A, 8-B]

Reagents:

Step 1: DBU, dppb, PdCl₂(PPh₃)₂, DMSO, 100° C. Step 2: LiOH.H₂O, MeOH,water, room temperature. Step 3: NH₂O-THP, EDC.HCl, HOBT, TEA,dichloromethane, room temperature. Step 4: 35.5% aq. HCl, EtOH, roomtemperature.

Step 1. Synthesis of ethyl3-(3-(4-(but-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[8a]

1d-A & 1d-B (0.5 g, 1.2 mmol, 1.0 equiv), pent-2-ynoic acid (0.12 g, 1.2mmol, 1.0 equiv), 1,4-bis(diphenylphosphino)butane (0.011 g, 0.027 mmol,0.02 equiv) were added in DMSO (5 mL). DBU (0.36 g, 2.4 mmol, 2.0 equiv)was added and the reaction mixture was degassed for 10 minutes.PdCl₂(PPh₃)₂ (0.009 g, 0.012 mmol, 0.01 equiv) was added and thereaction mixture was stirred at 100° C. for 2 hours. The reactionmixture was quenched with water and extracted with EtOAc. The organiclayer was washed with brine, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography (0-50%EtOAc in Hexane) to afford product 8a (0.4 g, 86.6% yield). LCMS (m/z):392.5 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.63 (dd, J=8.3, 1.4 Hz, 2H), 7.49(dd, J=22.5, 21.1 Hz, 2H), 4.99-4.71 (m, 1H), 4.34-4.10 (m, 2H), 3.59(td, J=17.2, 10.3 Hz, 1H), 3.26-2.96 (m, 4H), 2.67-2.54 (m, 1H), 2.46(q, J=7.5 Hz, 2H), 2.12 (ddd, J=17.2, 14.1, 5.9 Hz, 1H), 1.70-1.49 (m,3H), 1.25-1.15 (m, 6H).

Step 2. Synthesis of3-(3-(4-(but-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [8b]

8a (0.4 g, 1.0 mmol, 1.0 equiv) was dissolved in MeOH (4 mL) and water(2 mL). LiOH.H₂O (0.085 g, 2.0 mmol, 2.0 equiv) was added and thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was diluted with water, acidified by 1.0 N HCl aqueoussolution to the pH 4 to 5 and extracted with EtOAc. The organic layerwas washed with brine, dried over sodium sulfate and concentrated toafford product 8b (0.36 g, 96.9% yield) which was used in next stepwithout purification. LCMS (m/z): 364.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ7.67-7.58 (m, 2H), 7.46 (d, J=8.4 Hz, 2H), 4.94-4.87 (m, 1H), 3.61 (s,1H), 3.10 (d, J=14.7 Hz, 4H), 2.68 (s, 1H), 2.45 (s, 1H), 1.56 (d,J=17.9 Hz, 3H).

Step 3. Synthesis of3-(3-(4-(but-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[8c]

8b (0.35 g, 1.0 mmol, 1.0 equiv) was dissolved in dichloromethane (5mL). TEA (0.49 g, 4.8 mmol, 5.0 equiv), EDC.HCl (0.28 g, 1.4 mmol, 1.5equiv), HOBT (0.23 g, 1.7 mmol, 1.8 equiv), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.23 g, 1.9 mmol, 2.0 equiv) were added and the reactionmixture was stirred at room temperature for 24 hours. The reactionmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (0-4% MeOH indichloromethane) to afford product 8c (0.38 g, 85.3% yield). LCMS (m/z):463.6 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.62 (d, J=6.9 Hz, 2H), 7.46 (d,J=8.4 Hz, 2H), 4.95 (s, 1H), 4.85-4.75 (m, 1H), 4.06-3.99 (m, 1H), 3.56(s, 1H), 3.52 (s, 2H), 3.17-3.10 (m, 1H), 3.05 (t, J=7.3 Hz, 3H), 2.69(s, 1H), 2.05 (s, 1H), 1.65-1.54 (m, 9H).

Step 4. Synthesis of3-(3-(4-(but-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[8-A, 8-B]

8c (0.38 g, 0.8 mmol, 1.0 equiv) was dissolved in ethanol (2 mL). 35.5%aq. HCl (1 mL) was added and the reaction mixture was stirred at roomtemperature for 4 hours. The reaction mixture was then concentratedunder reduced pressure. The crude residue was purified by preparativeHPLC to afford 8 as two diastereomers (8-A, 0.07 g, 22.4% yield), LCMS(m/z): 379.2 [M+H]. ¹H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.15 (s,1H), 7.62 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 4.79 (s, 1H), 3.57(dd, J=16.9, 10.3 Hz, 1H), 3.16 (dd, J=17.1, 7.9 Hz, 1H), 3.11-2.95 (m,3H), 2.77-2.65 (m, 1H), 2.45 (d, J=7.4 Hz, 2H), 2.08-2.01 (m, 1H), 1.56(s, 3H), 1.18 (t, J=7.5 Hz, 3H). (8-B, 0.045 g, 14.4% yield), LCMS(m/z): 379.2 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 9.10 (s,1H), 7.61 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 3.54 (dd, J=17.0,10.4 Hz, 1H), 3.14 (dd, J=17.1, 7.9 Hz, 1H), 3.06 (s, 3H), 2.63 (dd,J=13.9, 3.7 Hz, 1H), 2.45 (d, J=7.5 Hz, 2H), 2.02 (dd, J=13.9, 8.1 Hz,1H), 1.56 (s, 3H), 1.18 (t, J=7.5 Hz, 3H).

Example 10. Synthesis ofN-hydroxy-3-(3-(4-(4-hydroxybut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide[10-A, 10-B]

Reagents:

Step 1: n-BuLi (2.5 M in hexane), CO₂, THF, −40° C. Step 2: DBU, dppb,PdCl₂(PPh₃)₂, DMSO, 100° C. Step 3: LiOH.H₂O, THF, MeOH, water, roomtemperature. Step 4: NH₂O-THP, EDC.HCl, HOBt, N-methyl morpholine, THF,room temperature. Step 5: 35.5% aq. HCl, EtOH, room temperature.

Step 1. Synthesis of 5-hydroxypent-2-ynoic acid [10a]

But-3-yn-1-ol (1 g, 14.3 mmol, 1.0 equiv) was dissolved in THF (10 mL)and the reaction mixture was cooled at −40° C. n-BuLi (2.5M in hexane)(6.8 mL, 17.1 mmol, 1.2 equiv) was added dropwise and the reactionmixture was stirred at −40° C. for 1 hour. The CO₂ gas was purged intoreaction mixture and stirred at −40° C. for 1 hour. The reaction mixturewas diluted with water, acidified by 35.5% aq. HCl solution to pH 3 to 4and extracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated to afford product 10a (0.9 g, 69.3%yield). The crude material was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO) δ 13.36 (s, 1H), 4.98 (s, 1H), 3.51(dt, J=13.9, 6.7 Hz, 2H), 2.57-2.50 (m, 2H).

Step 2. Synthesis of ethyl3-(3-(4-(4-hydroxybut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[10b]

1d-A & 1d-B (0.77 g, 1.8 mmol, 1.0 equiv), 5-hydroxypent-2-ynoic acid(0.21 g, 1.8 mmol, 1.0 equiv), 1,4-bis(diphenylphosphino)butane (0.014g, 0.04 mmol, 0.02 equiv) and DBU (0.56 g, 3.7 mmol, 2.0 equiv) wereadded in DMSO (10 mL) and the reaction mixture was degassed for 10minutes. PdCl₂(PPh₃)₂ (0.013 g, 0.02 mmol, 0.01 equiv) was added and thereaction mixture was stirred at 100° C. for 3 hours. The reactionmixture was quenched with water and extracted with EtOAc. The organiclayer was washed with brine, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography (30-50%EtOAc in Hexane) to afford product 10b (0.29 g, 74.5% yield). LCMS(m/z): 408.3 [M+H].

Step 3. Synthesis of3-(3-(4-(4-hydroxybut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [10c]

10b (0.290 g, 0.7 mmol, 1.0 equiv) was dissolved in THF (4 mL), MeOH (1mL) and water (1 mL). LiOH.H₂O (0.086 g, 2.1 mmol, 3.0 equiv) was addedand the reaction mixture was stirred at room temperature for 3 hours.The reaction mixture was diluted with water, acidified by 1.0 N HClaqueous solution to the pH 3 to 4 and extracted with EtOAc. The organiclayer was washed with brine, dried over sodium sulfate and concentratedto afford product 10c (0.23 g, 85.2% yield) which was used withoutpurification in next step. LCMS (m/z): 380.3 [M+H].

Step 4. Synthesis of3-(3-(4-(4-hydroxybut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[10d]

10c (0.18 g, 0.5 mmol, 1.0 equiv) was dissolved in THF (5 mL). N-methylmorpholine (0.24 g, 2.4 mmol, 5.0 equiv), EDC.HCl (0.14 g, 0.7 mmol, 1.5equiv), HOBT (0.12 g, 0.8 mmol, 1.8 equiv), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.11 g, 0.9 mmol, 2.0 equiv) were added and the reactionmixture was stirred at room temperature for 24 hours. The reaction wasthen quenched with water and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (1-2% MeOH indichloromethane) to afford product 10d (0.19 g, 63.8% yield). LCMS(m/z): 395.2 [M-THP].

Step 5. Synthesis ofN-hydroxy-3-(3-(4-(4-hydroxybut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide [10-A, 10-B]

10 d (0.14 g, 0.3 mmol, 1.0 equiv) was dissolved in ethanol (5 mL).35.5% aq. HCl (0.4 mL) was added and the reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was diluted withwater, neutralized by saturated aqueous sodium bicarbonate solution andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The crude product was purified bypreparative HPLC purification to afford 10 as two diastereomers. 10-A:0.023 g, 15.1% yield. LCMS (m/z): 395.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ10.81 (s, 1H), 9.16 (s, 1H), 7.62 (d, 2H), 7.47 (d, 2H), 4.96 (m, 1H),4.77 (m, 1H), 3.59 (s, 3H), 3.12 (m, 1H), 3.05 (s, 3H), 2.73 (m, 1H),2.58 (s, 2H), 2.07 (m, 1H), 1.55 (s, 3H). (10-B, 0.029 g, 19% yield),LCMS (m/z): 395.5 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.21-10.87 (m, 1H),9.55-9.21 (m, 1H), 7.62 (d, J=6.9 Hz, 2H), 7.47 (d, J=6.6 Hz, 2H), 4.94(m, 1H), 4.64 (m, 1H), 3.60 (s, 3H), 3.15 (s, 1H), 3.06 (s, 3H), 2.65(d, J=14.5 Hz, 1H), 2.58 (m, 2H), 2.04 (m, 1H), 1.58 (s, 3H).

Example 12. Synthesis of3-(3-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[12A, 12 B]

Reagents:

Step 1: NH₂OH.HCl, NaOH, water, 70° C. Step 2: Et₂Zn, (R,R)-DIPT,tBuOCl, chloroform,1,4-dioxane, 0° C. to room temperature. Step 3: DBU,dppb, PdCl₂(PPh₃)₂, DMSO, 90° C. Step 4: LiOH.H₂O, THF, MeOH, water,room temperature to 40° C. Step 5: NH₂O-THP, EDC.HCl, HOBt, N-methylmorpholine, THF, room temperature. Step 6: 35.5% aq. HCl, EtOH, roomtemperature.

Step 1. Synthesis of 4-bromo-3-fluorobenzaldehyde oxime [12a]

4-bromo-3-fluorobenzaldehyde (10 g, 49.2 mmol, 1.0 equiv) was added inwater (150 mL) and the reaction mixture was stirred at 70° C. A solutionof hydroxylamine hydrochloride (4.1 g, 59.1 mmol, 1.2 equiv) and sodiumhydroxide (2.56 g, 64.0 mmol, 1.3 equiv) in water (50 mL) was added tothe reaction mixture at same temperature and the reaction mixture wasstirred for 4 hours. The reaction mixture was cooled to roomtemperature. The precipitate was collected by filtration and then washedwith hexane to afford product 12a (7.5 g, 69.8% yield). LCMS (m/z):218.0 [M+H].

Step 2. Synthesis of ethyl3-(3-(4-bromo-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[12b]

A solution of 1b (6.9 g, 31.3 mmol, 1.0 equiv) in chloroform (80 mL) wascooled in a ice-water bath. Diethyl zinc (1M in hexane) (4.3 g, 34.1mmol, 1.1 equiv) was added and the reaction mixture was stirred at 0° C.for 20 minutes. (R,R)-DIPT (7.3 g, 31.3 mmol, 1.0 equiv) was added andthe reaction mixture was stirred at 0° C. for 1 hour. Diethyl zinc (1Min hexane) (4.3 g, 34.1 mmol, 1.1 equiv), 1,4-dioxane (4.14 g, 47.0mmol, 1.5 equiv) and 12a (6.8 g, 31.3 mmol, 1.0 equiv) in chloroform (20mL) were added slowly. t-BuOCl (6.8 g, 62.7 mmol, 2.0 equiv) was addedand the reaction mixture was stirred at room temperature for 24 hours.The reaction mixture was quenched with saturated aqueous ammoniumchloride solution and extracted with EtOAc. The organic layer was washedwith brine, dried over sodium sulfate and concentrated. The crudeproduct was purified by silica gel column chromatography (0-40% EtOAc inHexane) to afford product 12b (9.7 g, 70.9% yield). LCMS (m/z): 436.6[M+H]. ¹H NMR (400 MHz, DMSO) δ 7.82 (t, J=7.8 Hz, 1H), 7.63 (dt, J=9.8,1.7 Hz, 1H), 7.53-7.43 (m, 1H), 4.93-4.76 (m, 1H), 4.24 (ddd, J=10.6,10.0, 5.1 Hz, 2H), 3.66-3.54 (m, 1H), 3.23-3.17 (m, 1H), 3.11 (d, J=9.0Hz, 3H), 2.72-2.55 (m, 1H), 2.24-2.03 (m, 1H), 1.65-1.57 (m, 3H),1.22-1.17 (m, 3H).

Step 3. Synthesis of ethyl3-(3-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[12c]

12b (0.25 g, 0.6 mmol, 1.0 equiv), but-2-ynoic acid (0.057 g, 0.7 mmol,1.2 equiv), 1,4-bis(diphenylphosphino)butane (0.005 g, 0.013 mmol, 0.02equiv) were added in DMSO (9 mL). DBU (0.17 g, 1.1 mmol, 2.0 equiv) wasadded and the reaction mixture was degassed for 10 minutes. PdCl₂(PPh₃)₂(0.004 g, 0.006 mmol, 0.01 equiv) was added and the reaction mixture wasstirred at 90° C. for 6 hours. The reaction mixture was quenched withwater and extracted with EtOAc. The organic layer was washed with brine,dried over sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (0-40% EtOAc in Hexane) to affordproduct 12c (0.18 g, 79.3% yield). LCMS (m/z): 396.1 [M+H]. ¹H NMR (400MHz, DMSO) δ 7.64-7.44 (m, 3H), 4.91-4.73 (m, 1H), 4.23 (dq, J=29.2, 7.1Hz, 2H), 3.59 (ddd, J=20.1, 17.0, 10.3 Hz, 1H), 3.19 (dd, J=17.6, 6.3Hz, 1H), 3.12 (d, J=20.0 Hz, 3H), 2.68-2.55 (m, 1H), 2.14-1.98 (m, 4H),1.68-1.55 (m, 3H), 1.23-1.20 (m, 3H).

Step 4. Synthesis of3-(3-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [12d]

12c (0.18 g, 0.5 mmol, 1.0 equiv) was dissolved in THF (2 mL), MeOH (1mL) and water (1 mL). LiOH.H₂O (0.038 g, 0.9 mmol, 2.0 equiv) was addedand the reaction mixture was stirred at 40° C. for 2 hours. The reactionmixture was diluted with water and extracted with EtOAc. The aqueouslayer was acidified by 1.0 N HCl aqueous solution to the pH 3 to 4 andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. To the residue was then addedn-pentane. The solvent was decanted and the remaining material was driedto afford product 12d (0.16 g, 94.7% yield). LCMS (m/z): 368.4 [M+H]. ¹HNMR (400 MHz, DMSO) δ 13.64 (s, 1H), 7.53 (ddd, J=27.3, 17.5, 8.6 Hz,3H), 4.88 (d, J=56.3 Hz, 1H), 3.65-3.54 (m, 1H), 3.20 (dd, J=12.6, 5.0Hz, 1H), 3.12 (t, J=11.9 Hz, 3H), 2.64 (d, J=13.9 Hz, 1H), 2.27-2.00 (m,4H), 1.67-1.47 (m, 3H).

Step 5. Synthesis of3-(3-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[12e]

12d (0.16 g, 0.43 mmol, 1.0 equiv) was dissolved in THF (5 mL). N-methylmorpholine (0.22 g, 2.15 mmol, 5.0 equiv), EDC.HCl (0.12 g, 0.6 mmol,1.5 equiv), HOBT (0.069 g, 0.5 mmol, 1.2 equiv),O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.1 g, 0.8 mmol, 2.0 equiv)were added and the reaction mixture was stirred at room temperature for15 hours. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (0-5% MeOH in dichloromethane) to afford product 12e(0.16 g, 76.8% yield). LCMS (m/z): 467.4 [M+H]. ¹H NMR (400 MHz, DMSO) δ11.34 (s, 1H), 7.63-7.41 (m, 3H), 4.95 (s, 1H), 4.71 (s, 1H), 3.58 (s,1H), 3.44 (dd, J=7.1, 3.6 Hz, 2H), 3.19-3.11 (m, 1H), 3.11-2.96 (m, 3H),2.70 (d, J=14.0 Hz, 1H), 2.06 (d, J=9.9 Hz, 1H), 1.68 (d, J=13.8 Hz,3H), 1.44 (ddd, J=13.0, 6.6, 3.2 Hz, 6H).

Step 6. Synthesis of3-(3-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[12-A, 12-B]

12e (0.16 g, 0.34 mmol, 1.0 equiv) was dissolved in ethanol (5 mL).35.5% aq. HCl (0.3 mL) was added and the reaction mixture was stirred atroom temperature for 1.5 hours. The reaction mixture was diluted withwater, neutralized by saturated aqueous sodium bicarbonate solution andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The crude product was purified bypreparative HPLC purification to afford 12 as two diastereomers. 12-A:0.023 g, 17.6% yield. LCMS (m/z): 383.4 [M+H]. ¹H NMR (400 MHz, DMSO) δ10.87 (s, 1H), 9.15 (s, 1H), 7.64-7.41 (m, 3H), 4.80 (s, 1H), 3.57 (dd,J=17.0, 10.4 Hz, 1H), 3.16 (dd, J=17.1, 7.8 Hz, 1H), 3.11-2.99 (m, 3H),2.74 (dd, J=13.6, 8.4 Hz, 1H), 2.05 (dd, J=13.8, 4.5 Hz, 1H), 1.62-1.48(m, 3H). 12-B: 0.020 g, 15.3% yield. LCMS (m/z): 383.4 [M+H]. ¹H NMR(400 MHz, DMSO) δ 11.07 (s, 1H), 9.29 (s, 1H), 7.60-7.45 (m, 3H), 4.67(d, J=6.8 Hz, 1H), 3.58 (dd, J=17.0, 10.3 Hz, 1H), 3.14 (dd, J=17.3, 8.1Hz, 1H), 3.07 (s, 3H), 2.66 (d, J=14.2 Hz, 1H), 2.05 (dd, J=14.1, 8.5Hz, 1H), 1.59 (s, 3H).

Example 13. Synthesis of3-(3-(4-(cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[13-A, 13-B]

Reagents:

Step 1: DBU, dppb, PdCl₂(PPh₃)₂, DMSO, 100° C. Step 2: NaOH, MeOH, roomtemperature. Step 3: NH₂O-THP, EDC.HCl, HOBT, N-methyl morpholine, THF,room temperature. Step 4: 35.5% aq. HCl, EtOH, room temperature.

Step 1. Synthesis of ethyl3-(3-(4-(cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [13a]

12b (0.3 g, 0.7 mmol, 1.0 equiv), 3-cyclopropylpropiolic acid (0.075 g,0.7 mmol, 1.0 equiv), 1,4-bis(diphenylphosphino)butane (0.007 g, 0.015mmol, 0.02 equiv) were added in DMSO (8 mL). DBU (0.21 g, 1.3 mmol, 2.0equiv) was added and the reaction mixture was degassed for 10 minutes.PdCl₂(PPh₃)₂ (0.005 g, 0.007 mmol, 0.01 equiv) was added and thereaction mixture was stirred at 100° C. for 8 hours. The reactionmixture was quenched with water and extracted with EtOAc. The organiclayer was washed with brine, dried over sodium sulfate and concentratedto afford a crude residue. The residue was purified by silica gel columnchromatography (50-70% EtOAc in Hexane) to afford product 13a (0.21 g,72% yield). LCMS (m/z): 422.5 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.59-7.41(m, 3H), 4.92-4.73 (m, 1H), 4.28-4.17 (m, 2H), 3.58 (ddd, J=20.0, 17.1,10.3 Hz, 1H), 3.22-3.15 (m, 1H), 3.12 (d, J=20.0 Hz, 3H), 2.66-2.55 (m,1H), 2.20-2.04 (m, 1H), 1.71-1.55 (m, 4H), 1.25-1.22 (m, 3H), 0.98-0.91(m, 2H), 0.81-0.76 (m, 2H).

Step 2. Synthesis of3-(3-(4-(cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [13b]

13a (0.21 g, 0.5 mmol, 1.0 equiv) was dissolved in MeOH (5 mL). NaOH(0.039 g, 0.9 mmol, 2.0 equiv) was added and the reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture wasdiluted with water and extracted with EtOAc. The aqueous layer wasneutralized by 2.0 N HCl aqueous solution and extracted with EtOAc. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated to afford product 13b (0.17 g, 87% yield) which was usedwithout purification in next step. LCMS (m/z): 394.4 [M+H].

Step 3. Synthesis of3-(3-(4-(cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[13c]

13b (0.17 g, 0.43 mmol, 1.0 equiv) was dissolved in THF (8 mL). N-methylmorpholine (0.22 g, 2.16 mmol, 5.0 equiv), EDC.HCl (0.12 g, 0.6 mmol,1.5 equiv), HOBT (0.07 g, 0.5 mmol, 1.2 equiv),O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.1 g, 0.9 mmol, 2.0 equiv)were added and the reaction mixture was stirred at room temperature for24 hours. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated to afford a crude residue. The residue waspurified by silica gel column chromatography (50-70% EtOAc in Hexane) toafford product 13c (0.18 g, 89.5% yield). LCMS (m/z): 409.4 [M-THP]. ¹HNMR (400 MHz, DMSO) δ 11.58-11.22 (m, 1H), 7.60-7.42 (m, 3H), 5.21-5.07(m, 1H), 4.99-4.85 (m, 1H), 3.74 (qd, J=8.9, 4.6 Hz, 1H), 3.52 (ddd,J=12.6, 10.0, 4.1 Hz, 2H), 3.21-3.13 (m, 1H), 3.05 (dd, J=10.2, 4.7 Hz,3H), 2.70 (ddd, J=21.8, 14.0, 8.1 Hz, 1H), 2.12-2.03 (m, 1H), 1.70-1.45(m, 10H), 0.98-0.91 (m, 2H), 0.82-0.76 (m, 2H).

Step 4. Synthesis of3-(3-(4-(cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[13-A, 13-B]

13c (0.18 g, 0.36 mmol, 1.0 equiv) was dissolved in ethanol (5 mL).35.5% aq. HCl (0.2 mL) was added and the reaction mixture was stirred atroom temperature for 2 hours. The reaction mixture was diluted withwater, neutralized by saturated aqueous sodium bicarbonate solution andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated to afford crude residue. Theresidue was purified by preparative HPLC purification to afford 13 astwo diastereomers. 13-A: 0.028 g, 18.6% yield. LCMS (m/z): 409.3 [M+H].¹H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.14 (s, 1H), 7.62-7.40 (m, 3H),4.78 (d, J=4.5 Hz, 1H), 3.56 (dd, J=17.1, 10.4 Hz, 1H), 3.16 (dd,J=17.0, 7.9 Hz, 1H), 3.11-2.99 (m, 3H), 2.73 (dd, J=13.7, 8.4 Hz, 1H),2.05 (dd, J=13.9, 4.7 Hz, 1H), 1.63 (ddd, J=13.2, 8.2, 5.0 Hz, 1H), 1.53(d, J=20.1 Hz, 3H), 0.99-0.89 (m, 2H), 0.82-0.74 (m, 2H). 13-B: 0.020 g,13.4% yield. LCMS (m/z): 409.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.07 (s,1H), 9.29 (s, 1H), 7.58-7.42 (m, 3H), 4.66 (d, J=7.9 Hz, 1H), 3.57 (dd,J=17.1, 10.5 Hz, 1H), 3.13 (dd, J=17.2, 8.0 Hz, 1H), 3.06 (s, 3H),2.70-2.61 (m, 1H), 2.05 (dd, J=14.0, 8.5 Hz, 1H), 1.68-1.61 (m, 1H),1.59 (s, 3H), 0.95 (td, J=6.7, 4.1 Hz, 2H), 0.84-0.76 (m, 2H).

Example 14. Synthesis ofN-hydroxy-2-methyl-2-(methylsulfonyl)-3-(3-(5-(prop-1-yn-1-yl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)propanamide[14-A, 14-B]

Reagents:

Step 1: NH₂OH.HCl, Na₂CO₃, MeOH, water, room temperature. Step 2: NaOCl(14%), chloroform, 0° C. to room temperature. Step 3: DBU, dppb,PdCl₂(PPh₃)₂, DMSO, 120° C. Step 4: LiOH.H₂O, THF, MeOH, water, roomtemperature. Step 5: NH₂O-THP, EDC.HCl, HOBt, N-methyl morpholine, THF,room temperature. Step 6: 35.5% aq. HCl, EtOH, room temperature.

Step 1. Synthesis of 5-bromopicolinaldehyde oxime [14a]

5-Bromopicolinaldehyde (1 g, 5.4 mmol, 1.0 equiv) was dissolved in MeOH(18 mL) and water (2 mL). Hydroxylamine hydrochloride (0.45 g, 6.4 mmol,1.2 equiv), Sodium carbonate (0.57 g, 5.4 mmol, 1.0 equiv) in water (10mL) was added and the reaction mixture was stirred at room temperaturefor 3 hours. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated to afford product 14a (0.81 g, 75% yield) whichwas used without purification in next step. LCMS (m/z): 201.1 [M+H]. ¹HNMR (400 MHz, DMSO) δ 12.01-11.72 (m, 1H), 8.72 (d, J=2.2 Hz, 1H),8.30-7.91 (m, 2H), 7.75 (d, J=8.5 Hz, 1H).

Step 2. Synthesis of ethyl3-(3-(5-bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[14b]

14a (0.6 g, 3.0 mmol, 1.0 equiv) and 1b (0.72 g, 3.3 mmol, 1.1 equiv)were dissolved in chloroform (20 mL) and cooled to 0° C. NaOCl (14%)(0.45 g, 6.0 mmol, 2.0 equiv) was added and the reaction mixture wasstirred at room temperature for 24 hours. The reaction mixture wasquenched with saturated aqueous ammonium chloride solution and extractedwith EtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated to afford a crude product. The crude productwas purified by silica gel column chromatography (20-30% EtOAc inHexane) to afford product 14b (0.49 g, 33.6% yield). LCMS (m/z): 419.3[M+H]. ¹H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.18-8.09 (m, 1H), 7.87(d, J=8.6 Hz, 1H), 4.75 (s, 1H), 4.26-4.14 (m, 2H), 3.58 (s, 1H), 3.13(t, J=9.6 Hz, 3H), 2.96 (s, 1H), 2.67 (s, 1H), 2.09 (s, 1H), 1.61 (d,J=20.9 Hz, 3H), 1.27-1.24 (m, 4H).

Step 3. Synthesis of ethyl2-methyl-2-(methylsulfonyl)-3-(3-(5-(prop-1-yn-1-yl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)propanoate[14c]

14b (0.25 g, 0.6 mmol, 1.0 equiv), but-2-ynoic acid (0.055 g, 0.7 mmol,1.1 equiv), 1,4-bis(diphenylphosphino)butane (0.005 g, 0.012 mmol, 0.02equiv) were added in DMSO (5 mL). DBU (0.18 g, 1.2 mmol, 2.0 equiv) wasadded and the reaction mixture was degassed for 10 minutes. PdCl₂(PPh₃)₂(0.004 g, 0.006 mmol, 0.01 equiv) was added and the reaction mixture wasstirred at 120° C. for 2 hours. The reaction mixture was quenched withwater and extracted with EtOAc. The organic layer was washed with brine,dried over sodium sulfate and concentrated to afford a crude residue.The residue was purified by silica gel column chromatography (30-40%EtOAc in Hexane) to afford product 14c (0.17 g, 73.3% yield). LCMS(m/z): 379.4 [M+H].

Step 4. Synthesis of2-methyl-2-(methylsulfonyl)-3-(3-(5-(prop-1-yn-1-yl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)propanoicacid [14d]

14c (0.17 g, 0.4 mmol, 1.0 equiv) was dissolved in THF (2 mL), MeOH (1mL) and water (1 mL). LiOH.H₂O (0.055 g, 1.3 mmol, 3.0 equiv) was addedand the reaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was diluted with water, acidified by 1.0 N HCl aqueoussolution to the pH 5 to 6 and extracted with EtOAc. The organic layerwas washed with brine, dried over sodium sulfate and concentrated toafford product 14d (0.095 g, 62.5% yield) which was used withoutpurification in next step. LCMS (m/z): 351.3 [M+H]. ¹H NMR (400 MHz,DMSO) δ 14.24-13.67 (s, 1H), 8.63 (d, J=22.9 Hz, 1H), 7.97-7.82 (m, 2H),4.89 (d, J=51.3 Hz, 1H), 3.65-3.59 (m, 1H), 3.23 (d, J=8.7 Hz, 1H), 3.13(s, 3H), 2.59 (s, 1H), 2.14-2.03 (m, 4H), 1.57 (d, J=19.3 Hz, 3H).

Step 5. Synthesis of2-methyl-2-(methylsulfonyl)-3-(3-(5-(prop-1-yn-1-yl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[14e]

14d (0.095 g, 0.3 mmol, 1.0 equiv) was dissolved in THF (5 mL). N-methylmorpholine (0.14 g, 1.4 mmol, 5.0 equiv), EDC.HCl (0.078 g, 0.4 mmol,1.5 equiv), HOBT (0.066 g, 0.5 mmol, 1.8 equiv),O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.063 g, 0.5 mmol, 2.0equiv) were added and the reaction mixture was stirred at roomtemperature for 24 hours. The reaction mixture was quenched with waterand extracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The residue was purified by silicagel column chromatography (2-3% MeOH in dichloromethane) to affordproduct 14e (0.09 g, 73.8% yield) which was used directly in next step.LCMS (m/z): 366.4 [M-THP].

Step 6. Synthesis ofN-hydroxy-2-methyl-2-(methylsulfonyl)-3-(3-(5-(prop-1-yn-1-yl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)propanamide[14-A, 14-B]

14e (0.09 g, 0.2 mmol, 1.0 equiv) was dissolved in ethanol (5 mL). 35.5%aq. HCl (0.2 mL) was added and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was diluted with water,neutralized by saturated aqueous sodium bicarbonate solution andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated to afford crude residue. The cruderesidue was purified by preparative HPLC purification to afford 14 astwo diastereomers. 14-A: 0.009 g, 12.9% yield. LCMS (m/z): 366.4 [M+H].¹H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.15 (s, 1H), 8.66 (s, 1H), 7.87(s, 2H), 4.85 (s, 1H), 3.60 (d, J=7.1 Hz, 1H), 3.18 (dd, J=17.4, 8.2 Hz,1H), 3.05 (s, 3H), 2.71 (d, J=8.9 Hz, 1H), 2.10 (d, J=13.3 Hz, 4H), 1.56(s, 3H). 14-B: 0.014 g, 20% yield. LCMS (m/z): 366.4 [M+H]. ¹H NMR (400MHz, DMSO) δ 11.06 (s, 1H), 9.31 (s, 1H), 8.66 (s, 1H), 7.88 (s, 2H),4.69 (s, 1H), 3.59 (dd, J=17.5, 10.3 Hz, 1H), 3.19 (dd, J=17.9, 8.4 Hz,1H), 3.07 (s, 3H), 2.69 (d, J=10.6 Hz, 1H), 2.14-2.03 (m, 4H), 1.59 (s,3H).

Example 15. Synthesis of3-(3-(5-(cyclopropylethynyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[15-A, 15-B]

Reagents:

Step 1: DBU, dppb, PdCl₂(PPh₃)₂, DMSO, 120° C. Step 2: LiOH.H₂O, THF,MeOH, water, room temperature. Step 3: NH₂O-THP, EDC.HCl, HOBT, N-methylmorpholine, THF, room temperature. Step 4: 35.5% aq. HCl, EtOH, roomtemperature.

Step 1. Synthesis of ethyl3-(3-(5-(cyclopropylethynyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[15a]

14b (0.24 g, 0.6 mmol, 1.0 equiv), 3-cyclopropylpropiolic acid (0.069 g,0.7 mmol, 1.1 equiv), 1,4-bis(diphenylphosphino)butane (0.005 g, 0.012mmol, 0.02 equiv) were added in DMSO (5 mL). DBU (0.17 g, 1.1 mmol, 2.0equiv) was added and the reaction mixture was degassed for 10 minutes.PdCl₂(PPh₃)₂ (0.004 g, 0.006 mmol, 0.01 equiv) was added and thereaction mixture was stirred at 120° C. for 2 hours. The reactionmixture was quenched with water and extracted with EtOAc. The organiclayer was washed with brine, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography (30-40%EtOAc in Hexane) to afford product 15a (0.17 g, 73.6% yield).

Step 2. Synthesis of3-(3-(5-(cyclopropylethynyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [15b]

15a (0.17 g, 0.4 mmol, 1.0 equiv) was dissolved in THF (2 mL), MeOH (1mL) and water (1 mL). LiOH.H₂O (0.053 g, 1.3 mmol, 3.0 equiv) was addedand the reaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was diluted with water, acidified by 1.0 N HCl aqueoussolution to the pH 5 to 6 and extracted with EtOAc. The organic layerwas washed with brine, dried over sodium sulfate and concentrated toafford product 15b (0.1 g, 63.3% yield) which was used in next stepwithout purification. LCMS (m/z): 377.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ12.09 (s, 1H), 8.63 (s, 1H), 7.91 (d, J=44.3 Hz, 2H), 4.83 (s, 1H), 3.66(s, 1H), 3.19-3.05 (m, 3H), 2.95 (s, 1H), 2.19 (s, 1H), 1.81-1.45 (m,4H), 0.88 (d, J=55.2 Hz, 4H).

Step 3. Synthesis of3-(3-(5-(cyclopropylethynyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[15c]

15b (0.1 g, 0.3 mmol, 1.0 equiv) was dissolved in THF (5 mL). N-methylmorpholine (0.13 g, 1.3 mmol, 5.0 equiv), EDC.HCl (0.076 g, 0.4 mmol,1.5 equiv), HOBT (0.065 g, 0.5 mmol, 1.8 equiv),O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.062 g, 0.5 mmol, 2.0equiv) were added and the reaction mixture was stirred at roomtemperature for 24 hours. The reaction mixture was quenched with waterand extracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The residue was purified by silicagel column chromatography (2-3% MeOH in dichloromethane) to affordproduct 15c (0.09 g, 71.4% yield). LCMS (m/z): 392.4 [M-THP].

Step 4. Synthesis of3-(3-(5-(cyclopropylethynyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[15-A, 15-B]

15c (0.09 g, 0.2 mmol, 1.0 equiv) was dissolved in ethanol (5 mL). 35.5%aq. HCl (0.2 mL) was added and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was diluted with water,neutralized by saturated aqueous sodium bicarbonate solution andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The crude residue was purified bypreparative HPLC purification to afford 15 as two diastereomers. 15-A:0.007 g, 9.5% yield. LCMS (m/z): 392.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ10.86 (s, 1H), 9.15 (s, 1H), 8.62 (s, 1H), 7.85 (s, 2H), 4.84 (s, 1H),3.59 (s, 1H), 3.21-3.15 (m, 1H), 3.05 (s, 3H), 2.68 (s, 1H), 2.08 (s,1H), 1.56 (s, 4H), 0.89 (dd, J=41.2, 13.1 Hz, 4H). 15-B: 0.010 g, 13.5%yield. LCMS (m/z): 392.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.06 (s, 1H),9.31 (s, 1H), 8.62 (s, 1H), 7.85 (s, 2H), 4.70 (s, 1H), 3.58 (dd,J=17.6, 10.4 Hz, 1H), 3.18 (dd, J=17.8, 8.1 Hz, 1H), 3.12-3.02 (m, 3H),2.68 (d, J=10.8 Hz, 1H), 2.06 (dd, J=13.8, 8.3 Hz, 1H), 1.66-1.54 (m,4H), 0.94 (dd, J=8.2, 2.7 Hz, 2H), 0.80 (dd, J=4.8, 2.5 Hz, 2H).

Example 16. Synthesis of3-(3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[16-A, 16-B]

Reagents:

Step 1: NH₂OH.HCl, NaOH, water, 80° C. Step 2: NaOCl, THF, roomtemperature. Step 3: DBU, dppb, PdCl₂(PPh₃)₂, DMSO, 120° C. Step 4:LiOH.H₂O, THF, MeOH, water, room temperature. Step 5: NH₂O-THP, EDC.HCl,HOBT, N-methyl morpholine, THF, room temperature. Step 6: 35.5% aq. HCl,EtOH, room temperature.

Step 1. Synthesis of 4-bromo-2-fluorobenzaldehyde oxime [16a]

4-bromo-2-fluorobenzaldehyde (10 g, 49.2 mmol, 1.0 equiv) was dissolvedin water (80 mL) and the reaction mixture was stirred at 70° C. Asolution of hydroxylamine hydrochloride (6.6 g, 98 mmol, 2.0 equiv) andsodium hydroxide (3.94 g, 98 mmol, 2.0 equiv) in water (20 mL) was addedto the reaction mixture at same temperature. The reaction mixture wasstirred at 70° C. for 6 hours. The reaction mixture was cooled to roomtemperature and filtered. The collected solid was triturated withhexane, the solvent was decanted and dried to afford product 16a (9.12g, 84% yield) which was used in next step without purification. ¹H NMR(400 MHz, DMSO) δ 11.71 (d, J=19.9 Hz, 1H), 8.16 (d, J=20.1 Hz, 1H),7.78-7.58 (m, 2H), 7.52-7.41 (m, 1H).

Step 2. Synthesis of ethyl3-(3-(4-bromo-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[16b]

16a (6 g, 25 mmol, 1.0 equiv) was dissolved in THF (50 mL). 1b (5.6 g,25 mmol, 1.0 equiv) and sodium hypochlorite (7.6 g, 50 mmol, 2.0 equiv)were added and the reaction mixture was stirred at room temperature for6 hours. The reaction mixture was quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The crude residue was purified by silica gelcolumn chromatography (10-15% EtOAc in Hexane) to afford product 16b (8g, 68% yield). LCMS (m/z): 436.4 [M+H]. ¹H NMR (400 MHz, DMSO) δ7.78-7.65 (m, 2H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 4.84 (dd, J=68.4, 8.4Hz, 1H), 4.29-4.16 (m, 2H), 3.63 (dd, J=16.7, 8.5 Hz, 1H), 3.21 (d,J=17.3 Hz, 1H), 3.17-3.09 (m, 3H), 2.68-2.57 (m, 1H), 2.25-2.10 (m, 1H),1.63 (t, J=20.8 Hz, 3H).

Step 3. Synthesis of ethyl3-(3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[16c]

16b (0.6 g, 1.37 mmol, 1.0 equiv), but-2-ynoic acid (0.25 g, 2.75 mmol,2.0 equiv), 1,4-bis(diphenylphosphino)butane (0.009 g, 0.027 mmol, 0.02equiv) were added in DMSO (10 mL). DBU (0.41 g, 2.7 mmol, 2.0 equiv) wasadded and the reaction mixture was degassed for 10 minutes. PdCl₂(PPh₃)₂(0.012 g, 0.014 mmol, 0.01 equiv) was added and the reaction mixture wasstirred at 120° C. for 12 hours. The reaction mixture was quenched withwater and extracted with EtOAc. The organic layer was washed with brine,dried over sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (20-25% EtOAc in Hexane) to affordproduct 16c (0.42 g, 77% yield). LCMS (m/z): 396.4 [M+H]. ¹H NMR (400MHz, DMSO) δ 7.69 (t, J=7.4 Hz, 1H), 7.34 (dd, J=29.6, 9.5 Hz, 2H), 4.83(d, J=67.9 Hz, 1H), 4.23 (dq, J=24.8, 7.1 Hz, 2H), 3.22 (s, 1H),3.16-3.07 (m, 3H), 2.65-2.58 (m, 1H), 2.20 (dd, J=14.5, 8.5 Hz, 1H),1.60 (d, J=21.6 Hz, 3H), 1.24 (dt, J=9.2, 7.1 Hz, 3H).

Step 4. Synthesis of3-(3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [16d]

16c (0.42 g, 1.0 mmol, 1.0 equiv) was dissolved in THF (6 mL), MeOH (2mL) and water (2 mL). LiOH.H₂O (0.069 g, 1.6 mmol, 1.5 equiv) was addedand the reaction mixture was stirred at room temperature for 3 hours.The reaction mixture was acidified by 1.0 N HCl aqueous solution to thepH 3 to 4 and extracted with EtOAc. The organic layer was washed withbrine, dried over sodium sulfate and concentrated to afford product 16d(0.35 g, 92% yield) which was used in next step without purification.LCMS (m/z): 368.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 7.68(td, J=8.0, 3.3 Hz, 1H), 7.33 (dd, J=28.9, 10.1 Hz, 2H), 4.83 (dd,J=55.1, 8.4 Hz, 1H), 3.67-3.55 (m, 1H), 3.20 (dd, J=17.1, 7.3 Hz, 1H),3.11 (d, J=15.3 Hz, 3H), 2.62 (dd, J=13.9, 10.1 Hz, 1H), 2.20-2.04 (m,4H), 1.54 (t, J=18.6 Hz, 3H).

Step 5. Synthesis of3-(3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[16e]

16d (0.35 g, 0.95 mmol, 1.0 equiv) was dissolved in THF (10 mL).N-methyl morpholine (0.48 g, 4.76 mmol, 5.0 equiv), EDC.HCl (0.33 g, 1.7mmol, 1.8 equiv), HOBT (0.19 g, 1.43 mmol, 1.5 equiv),O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.22 g, 1.9 mmol, 2.0 equiv)were added and the reaction mixture was stirred at room temperature for24 hours. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (30-40% EtOAc in Hexane) to afford product 16e (0.3 g,68% yield). LCMS (m/z): 383.6 [M-THP]. ¹H NMR (400 MHz, DMSO) δ 11.34(s, 1H), 7.68 (d, J=6.0 Hz, 1H), 7.33 (dd, J=28.6, 9.9 Hz, 2H), 5.13 (d,J=34.3 Hz, 1H), 4.84 (d, J=26.2 Hz, 1H), 3.58 (s, 1H), 3.47 (d, J=10.2Hz, 2H), 3.17 (d, J=18.0 Hz, 1H), 3.09-3.02 (m, 3H), 2.70 (d, J=14.0 Hz,1H), 2.06 (d, J=20.6 Hz, 4H), 1.69 (s, 3H), 1.49 (d, J=33.0 Hz, 6H).

Step 6. Synthesis of3-(3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[16-A, 16-B]

16e (0.3 g, 0.64 mmol, 1.0 equiv) was dissolved in ethanol (10 mL).35.5% aq. HCl (0.2 mL) was added and the reaction mixture was stirred atroom temperature for 4 hours. The reaction mixture was diluted withwater, neutralized by saturated aqueous sodium bicarbonate solution andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The crude residue was purified bypreparative HPLC purification to afford 16 as two diastereomers. 16-A:0.030 g, 12.5% yield. LCMS (m/z): 383.4 [M+18]. ¹H NMR (400 MHz, DMSO) δ10.84 (s, 1H), 9.15 (s, 1H), 7.68 (t, J=7.9 Hz, 1H), 7.33 (dd, J=28.0,9.9 Hz, 2H), 4.77 (s, 1H), 3.60 (dd, J=16.6, 10.7 Hz, 1H), 3.18 (dd,J=16.7, 7.6 Hz, 1H), 3.14-2.89 (m, 3H), 2.72 (d, J=15.4 Hz, 1H), 2.15(d, J=55.6 Hz, 4H), 1.55 (s, 3H). 16-B: 0.028 g, 11.7% yield), LCMS(m/z): 383.4 [M+18]. ¹H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 9.28 (s,1H), 7.68 (t, J=8.0 Hz, 1H), 7.33 (dd, J=28.4, 10.0 Hz, 2H), 4.63 (d,J=7.8 Hz, 1H), 3.69-3.58 (m, 1H), 3.18 (dd, J=16.9, 7.6 Hz, 1H),3.12-2.99 (m, 3H), 2.75-2.64 (m, 1H), 2.17-1.91 (m, 4H), 1.75-1.49 (m,3H).

Example 17. Synthesis of3-(3-(4-(cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[17-A, 17-B]

Reagents:

Step 1: DBU, dppb, PdCl₂(PPh₃)₂, DMSO, 120° C. Step 2: LiOH.H₂O, THF,MeOH, water, room temperature. Step 3: NH₂O-THP, EDC.HCl, HOBt, N-methylmorpholine, THF, room temperature. Step 4: 35.5% aq. HCl, EtOH, roomtemperature.

Step 1. Synthesis of ethyl3-(3-(4-(cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [17a]

16b (0.6 g, 1.3 mmol, 1.0 equiv), 3-cyclopropylpropiolic acid (0.3 g,2.7 mmol, 2.0 equiv), 1,4-bis(diphenylphosphino)butane (0.011 g, 0.027mmol, 0.02 equiv) were added in DMSO (10 mL). DBU (0.41 g, 2.7 mmol, 2.0equiv) was added and the reaction mixture was degassed for 10 minutes.PdCl₂(PPh₃)₂ (0.009 g, 0.014 mmol, 0.01 equiv) was added and thereaction mixture was stirred at 120° C. for 15 hours. The reactionmixture was quenched with water and extracted with EtOAc. The organiclayer was washed with brine, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography (20-22%EtOAc in Hexane) to afford product 17a (0.54 g, 93% yield). LCMS (m/z):422.4 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.68 (t, J=7.5 Hz, 1H), 7.46-7.21(m, 2H), 4.99-4.70 (m, 1H), 4.30-4.16 (m, 2H), 3.67-3.54 (m, 1H), 3.21(d, J=9.5 Hz, 1H), 3.15-3.07 (m, 3H), 2.61 (ddd, J=18.2, 12.9, 9.6 Hz,1H), 2.13 (ddd, J=17.2, 14.2, 5.8 Hz, 1H), 1.71-1.50 (m, 4H), 1.24 (dt,J=9.7, 7.1 Hz, 3H), 0.98-0.86 (m, 2H), 0.83-0.73 (m, 2H).

Step 2. Synthesis of3-(3-(4-(cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [17b]

17a (0.54 g, 1.2 mmol, 1.0 equiv) was dissolved in THF (6 mL), MeOH (2mL) and water (2 mL). LiOH.H₂O (0.08 g, 1.9 mmol, 1.5 equiv) was addedand the reaction mixture was stirred at room temperature for 4 hours.The reaction mixture was acidified by 1.0 N HCl aqueous solution to thepH 3 to 4 and extracted with EtOAc. The organic layer was washed withbrine, dried over sodium sulfate and concentrated to afford product 17b(0.45 g, 83% yield) which was used in next step without purification.LCMS (m/z): 394.4 [M+H].

Step 3. Synthesis of3-(3-(4-(cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[17c]

17b (0.45 g, 1.14 mmol, 1.0 equiv) was dissolved in THF (10 mL).N-methyl morpholine (0.58 g, 5.71 mmol, 5.0 equiv), EDC.HCl (0.39 g,2.05 mmol, 1.8 equiv), HOBT (0.23 g, 1.72 mmol, 1.5 equiv),O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.27 g, 2.28 mmol, 2.0equiv) were added and the reaction mixture was stirred at roomtemperature for 24 hours. The reaction mixture was quenched with waterand extracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The residue was purified by silicagel column chromatography (30-50% EtOAc in Hexane) to afford product 17c(0.42 g, 75% yield). LCMS (m/z): 491.5 [M+H]. ¹H NMR (400 MHz, DMSO) δ11.46 (s, 1H), 7.67 (d, J=6.9 Hz, 1H), 7.30 (dd, J=29.9, 10.0 Hz, 2H),5.12 (d, J=29.4 Hz, 1H), 4.84 (d, J=25.4 Hz, 1H), 3.75 (d, J=11.1 Hz,1H), 3.53 (d, J=36.4 Hz, 2H), 3.21-3.13 (m, 1H), 3.05 (dd, J=8.7, 4.5Hz, 3H), 2.68 (s, 1H), 2.06 (s, 1H), 1.79-1.64 (m, 4H), 1.56 (dd,J=15.3, 8.9 Hz, 6H), 0.93 (dt, J=6.3, 4.0 Hz, 2H), 0.81-0.75 (m, 2H).

Step 4. Synthesis of3-(3-(4-(cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[17-A, 17-B]

17c (0.42 g, 0.87 mmol, 1.0 equiv) was dissolved in ethanol (10 mL).35.5% aq. HCl (0.2 mL) was added and the reaction mixture was stirred atroom temperature for 4 hours. The reaction mixture was diluted withwater, neutralized by saturated aqueous sodium bicarbonate solution andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated to afford crude residue. The cruderesidue was purified by preparative HPLC purification to afford 17 astwo diastereomers. 17-A: 0.080 g, 25.6% yield), LCMS (m/z): 409.4 [M+H].¹H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.14 (s, 1H), 7.67 (t, J=7.6 Hz,1H), 7.30 (dd, J=27.7, 9.8 Hz, 2H), 4.77 (s, 1H), 3.59 (dd, J=16.8, 10.7Hz, 1H), 3.17 (dd, J=16.5, 7.5 Hz, 1H), 3.03 (d, J=19.7 Hz, 3H),2.85-2.61 (m, 1H), 2.08 (d, J=10.4 Hz, 1H), 1.90-1.22 (m, 4H), 1.19-0.48(m, 4H). 17-B: 0.070 g, 22.4% yield. LCMS (m/z): 409.4 [M+H]. ¹H NMR(400 MHz, DMSO) δ 11.01 (s, 1H), 9.28 (s, 1H), 7.67 (t, J=8.0 Hz, 1H),7.49-7.20 (m, 2H), 4.63 (dd, J=15.5, 8.1 Hz, 1H), 3.59 (dd, J=16.8, 10.1Hz, 1H), 3.26-3.14 (m, 1H), 3.11-2.88 (m, 3H), 2.67 (dd, J=14.0, 3.1 Hz,1H), 2.13-1.94 (m, 1H), 1.77-1.33 (m, 4H), 1.05-0.64 (m, 4H).

Example 22. Synthesis of(R)-3-((R)-3-(4-(4-fluorobut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide22

Reagents:

Step 1: Diethyl amine, triphenyl phosphine, CuI, PdCl₂(pph₃)₂,N,N-dimethylformamide, 100° C. Step 2: DAST, dichloromethane, −78° C. toroom temperature. Step 3: LiOH.H₂O, THF, MeOH, water, room temperature.Step 4: NH₂OTHP, EDC.HCl, HOBT, N-methyl morpholine, THF, roomtemperature. Step 5: HCl (in IPA), MeOH, dichloromethane, roomtemperature.

Step 1. Synthesis of (R)-ethyl3-((R)-3-(4-(4-hydroxybut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[22a]

(R)-1d-A (0.25 g, 0.59 mmol, 1.0 equiv) was added with diethyl amine (10ml) and N,N-dimethylformamide (2 mL). CuI (0.011 g, 0.059 mmol, 0.1equiv), triphenyl phosphine (0.031 g, 0.12 mmol, 0.2 equiv) were addedand the reaction mixture was degassed for 10 minutes. PdCl₂(pph₃)₂ (0.02g, 0.03 mmol, 0.05 equiv), but-3-yn-1-ol (0.083 g, 1.19 mmol, 2.0 equiv)were added and the reaction mixture was stirred at 100° C. for 2 hours.The reaction mixture was quenched with water and extracted with EtOAc.The organic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (50-55% EtOAc/Hexane) to afford product 22a (0.2 g, 82%yield). LCMS (m/z): 408.2 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.63 (dd,J=8.1, 4.3 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 4.94 (t, J=5.6 Hz, 1H), 4.76(td, J=11.3, 3.3 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.65-3.53 (m, 3H),3.22-3.06 (m, 4H), 2.59 (dd, J=12.9, 6.1 Hz, 3H), 2.21-2.14 (m, 1H),1.61 (d, J=22.3 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of (R)-ethyl3-((R)-3-(4-(4-fluorobut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[22b]

22a (0.18 g, 0.44 mmol, 1.0 equiv) was dissolved in dichloromethane (10mL) and cooled to −78° C. DAST (0.14 g, 0.88 mmol, 2.0 equiv) was addeddropwisely and the reaction mixture was stirred at room temperature for12 hours. The reaction mixture was poured to water, neutralized withsaturated aqueous sodium bicarbonate solution and extracted with EtOAc.The organic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (25-30% EtOAc/Hexane) to afford product 22b (0.08 g, 45%yield). LCMS (m/z): 410.1 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.64 (d, J=8.4Hz, 2H), 7.51 (t, J=10.8 Hz, 2H), 4.76 (ddd, J=18.8, 8.4, 3.3 Hz, 1H),4.65 (t, J=6.0 Hz, 1H), 4.54 (t, J=6.0 Hz, 1H), 4.33-4.18 (m, 2H), 3.61(dd, J=17.0, 10.4 Hz, 1H), 3.24-3.04 (m, 4H), 2.93 (t, J=6.0 Hz, 1H),2.87 (t, J=6.0 Hz, 1H), 2.59 (dd, J=14.5, 3.2 Hz, 1H), 2.18 (dd, J=9.3,5.2 Hz, 1H), 1.61 (d, J=22.2 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H).

Step 3. Synthesis of(R)-3-((R)-3-(4-(4-fluorobut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [22c]

22b (0.08 g, 0.19 mmol, 1.0 equiv) was dissolved in THF (4 mL), MeOH (1mL) and water (1 mL). LiOH.H₂O (0.024 g, 0.58 mmol, 3.0 equiv) was addedand the reaction mixture was stirred at room temperature for 2 hours.The reaction mixture was poured to water, acidified by 1.0 N HCl aqueoussolution up to pH 4 to 5 and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated to affordproduct 22c (0.065 g, 87% yield). The product was directly used in thenext step with no further purification. LCMS (m/z): 382.1 [M+H]. ¹H NMR(400 MHz, DMSO) δ 14.03 (s, 1H), 7.67-7.60 (m, 2H), 7.52 (dd, J=22.8,8.4 Hz, 2H), 4.77 (d, J=7.4 Hz, 1H), 4.65 (t, J=6.0 Hz, 1H), 4.54 (t,J=6.0 Hz, 1H), 3.63 (dd, J=17.0, 10.4 Hz, 1H), 3.23-3.16 (m, 1H), 3.14(d, J=7.7 Hz, 3H), 2.93 (t, J=6.0 Hz, 1H), 2.87 (t, J=6.1 Hz, 1H), 2.56(s, 1H), 2.20-2.14 (m, 1H), 1.60 (s, 3H).

Step 4. Synthesis of(2R)-3-((R)-3-(4-(4-fluorobut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[22d]

22c (0.065 g, 0.17 mmol, 1.0 equiv) was dissolved in THF (5 mL).N-methyl morpholine (0.086 g, 0.852 mmol, 5.0 equiv), HOBT (0.027 g, 0.2mmol, 1.2 equiv), O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.04 g,0.34 mmol, 2.0 equiv), EDC.HCl (0.048 g, 0.26 mmol, 1.5 equiv) wereadded and the reaction mixture was stirred at room temperature for 24hours. The reaction mixture was quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (30-40% EtOAc/Hexane) to afford product 22d (0.065 g, 79%yield). LCMS (m/z): 498.3 [M+18]. ¹H NMR (400 MHz, DMSO) δ 11.47 (s,1H), 7.71-7.59 (m, 2H), 7.52 (dd, J=23.0, 8.4 Hz, 2H), 4.97 (d, J=8.3Hz, 1H), 4.65 (t, J=6.0 Hz, 2H), 4.53 (t, J=6.0 Hz, 1H), 4.05 (dt,J=14.3, 9.8 Hz, 2H), 3.64-3.49 (m, 2H), 3.15 (dd, J=17.3, 7.7 Hz, 1H),3.06 (d, J=8.7 Hz, 3H), 2.90 (dt, J=24.2, 6.1 Hz, 2H), 2.68 (d, J=12.3Hz, 1H), 2.07 (dd, J=13.0, 8.4 Hz, 1H), 1.70 (s, 3H), 1.61 (d, J=4.3 Hz,3H), 1.54 (s, 3H).

Step 5. Synthesis of(R)-3-((R)-3-(4-(4-fluorobut-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[22]

22d (0.065 g, 0.14 mmol, 1.0 equiv) was dissolved in methanol (2 mL) anddichloromethane (2 mL). 10% HCl (in IPA) (0.02 mL) was added and thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was quenched with water, neutralized by saturatedaqueous sodium bicarbonate solution and extracted with EtOAc. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was triturated with n-pentane/diethyl ether.The solvent was decanted and the remaining material was dried to affordproduct 22 (0.02 g, 38% yield). LCMS (m/z): 397.2 [M+H]. ¹H NMR (400MHz, DMSO) δ 11.07 (s, 1H), 9.29 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.50(d, J=8.4 Hz, 2H), 4.65 (t, J=6.0 Hz, 2H), 4.54 (t, J=6.0 Hz, 1H), 3.58(dd, J=17.0, 10.5 Hz, 1H), 3.14 (dd, J=17.0, 8.1 Hz, 1H), 3.07 (s, 3H),2.93 (t, J=6.0 Hz, 1H), 2.87 (t, J=6.0 Hz, 1H), 2.70-2.62 (m, 1H), 2.04(dd, J=14.0, 8.4 Hz, 1H), 1.59 (s, 3H).

Example 23. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-propylphenyl)-4,5-dihydroisoxazol-5-yl)propanamide[23]

Reagents:

Step 1: CuI, PdCl₂(dppf), THF, 160° C. (MW). Step 2: LiOH.H₂O, THF,MeOH, water, room temperature. Step 3: NH₂OTHP, EDC.HCl, HOBT, N-methylmorpholine, THF, room temperature. Step 4: HCl (in IPA), MeOH,dichloromethane, 10° C. to room temperature.

Step 1. Synthesis of (R)-ethyl2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-propylphenyl)-4,5-dihydroisoxazol-5-yl)propanoate[23a]

(R)-1d-A (0.2 g, 0.47 mmol, 1.0 equiv) was dissolved in THF (1 mL). CuI(0.005 g, 0.024 mmol, 0.05 equiv), PdCl₂ (dppf) (0.017 g, 0.024 mmol,0.05 equiv), propylzinc (II) bromide (5.0M in THF) (1.9 mL, 9.56 mmol,20.0 equiv) were added and the reaction mixture was stirred at 160° C.for 10 minutes under microwave irradiation. The reaction mixture wasfiltered through Celite, washed with EtOAc. The filtrate was dilutedwith water and extracted with EtOAc. The organic layer was washed withbrine, dried over sodium sulfate and concentrated. The residue waspurified by silica gel column chromatography (15% EtOAc/Hexane) toafford product 23a (0.1 g, 55% yield). LCMS (m/z): 382.2 [M+H]. ¹H NMR(400 MHz, DMSO) δ 7.57 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 4.72(dt, J=11.3, 5.5 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.60 (dd, J=16.9, 10.3Hz, 1H), 3.22-3.08 (m, 4H), 2.59 (dd, J=9.3, 5.5 Hz, 3H), 2.17 (dd,J=14.4, 8.5 Hz, 1H), 1.71-1.53 (m, 5H), 1.26 (t, J=7.1 Hz, 3H), 0.89 (t,J=7.3 Hz, 3H).

Step 2. Synthesis of(R)-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-propylphenyl)-4,5-dihydroisoxazol-5-yl)propanoicacid [23b]

23a (0.1 g, 0.26 mmol, 1.0 equiv) was dissolved in THF (5 mL), MeOH (1mL) and water (1 mL). LiOH.H₂O (0.022 g, 0.52 mmol, 2.0 equiv) was addedand the reaction mixture was stirred at room temperature for 2 hours.The reaction mixture was acidified by 1.0 N HCl aqueous solution to pH 3to 4 and extracted with EtOAc. The organic layer was washed with brine,dried over sodium sulfate and concentrated to afford product 23b (0.09g, 97.8% yield). LCMS (m/z): 354.2 [M+H]. The product was directly usedin the next step with no further purification. ¹H NMR (400 MHz, DMSO) δ7.55 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 4.77-4.68 (m, 1H), 3.58(dd, J=17.0, 10.3 Hz, 1H), 3.19-3.12 (m, 1H), 3.10 (d, J=4.6 Hz, 3H),2.57 (t, J=7.5 Hz, 3H), 2.11 (dd, J=14.3, 8.5 Hz, 1H), 1.63-1.46 (m,5H), 0.86 (t, J=7.3 Hz, 3H).

Step 3. Synthesis of(2R)-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-propylphenyl)-4,5-dihydroisoxazol-5-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[23c]

23b (0.09 g, 0.25 mmol, 1.0 equiv) was dissolved in THF (5 mL). N-methylmorpholine (0.13 g, 1.3 mmol, 5.0 equiv), HOBT (0.041 g, 0.31 mmol, 1.2equiv), O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.06 g, 0.5 mmol,2.0 equiv), EDC.HCl (0.073 g, 0.38 mmol, 1.5 equiv) were added and thereaction mixture was stirred at room temperature for 24 hours. Thereaction mixture was quenched with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (30% EtOAc/Hexane) to afford product 23c (0.09 g, 78.3%yield). LCMS (m/z): 369.3 [M-THP]. ¹H NMR (400 MHz, DMSO) δ 11.46 (s,1H), 7.56 (d, J=7.5 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 4.98 (d, J=9.3 Hz,1H), 4.64 (d, J=6.9 Hz, 1H), 4.07 (dd, J=28.7, 6.2 Hz, 1H), 3.63-3.46(m, 2H), 3.14 (dd, J=16.9, 8.0 Hz, 1H), 3.06 (d, J=8.5 Hz, 3H), 2.67 (d,J=14.3 Hz, 1H), 2.59 (t, J=7.5 Hz, 2H), 2.06 (dd, J=14.3, 8.8 Hz, 1H),1.70 (s, 3H), 1.64-1.51 (m, 8H), 0.89 (t, J=7.3 Hz, 3H).

Step 4. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-propylphenyl)-4,5-dihydroisoxazol-5-yl)propanamide[23]

23c (0.09 g, 0.19 mmol, 1.0 equiv) was dissolved in dichloromethane (2mL), methanol (0.5 mL) and the reaction mixture was cooled to 10° C. 10%HCl (in IPA) (0.2 mL) was added and the reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was neutralized bysaturated aqueous sodium bicarbonate solution and extracted with EtOAc.The organic layer was washed with brine, dried over sodium sulfate andconcentrated to afford crude residue. The residue was triturated withn-pentane and diethyl ether. The solvent was decanted and the remainingsolid was dried under vacuum to afford product 23 (0.043 g, 56.6%yield). LCMS (m/z): 369.2 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.11 (s, 1H),9.11 (s, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 4.63 (s,1H), 3.53 (dd, J=16.6, 10.0 Hz, 1H), 3.13 (dd, J=16.7, 7.7 Hz, 1H), 3.06(s, 3H), 2.70-2.55 (m, 3H), 2.02 (dd, J=13.8, 8.1 Hz, 1H), 1.60 (dd,J=16.0, 8.4 Hz, 5H), 0.89 (t, J=7.3 Hz, 3H).

Example 24. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-((E)-prop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[24]

Reagents:

Step 1: Cs₂CO₃, PdCl₂(dppf), 1,4-dioxane, 100° C. Step 2: LiOH.H₂O, THF,MeOH, water, room temperature. Step 3: NH₂OTHP, EDC.HCl, HOBT, N-methylmorpholine, THF, room temperature. Step 4: HCl (in IPA), MeOH,dichloromethane, room temperature.

Step 1. Synthesis of (R)-ethyl2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-((E)-prop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanoate[24a]

(R)-1d-A (0.2 g, 0.48 mmol, 1.0 equiv) and Cs₂CO₃ (0.47 g, 1.43 mmol,3.0 equiv) were added in 1, 4-dioxane (10 mL). (E)-prop-1-en-1-ylboronicacid (0.05 g, 0.57 mmol, 1.2 equiv) was added and the reaction mixturewas degassed for 10 minutes. PdCl₂(dppf) (0.024 g, 0.033 mmol, 0.07equiv) was added and the reaction mixture was stirred at 100° C. for 24hours. The reaction mixture was quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (25-35% EtOAc/Hexane) to afford product 24a (0.15 g, 80%yield). LCMS (m/z): 380.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.67 (s, 1H),7.59 (d, J=8.1 Hz, 1H), 7.47 (s, 2H), 6.47 (d, J=16.0 Hz, 1H), 4.74 (s,1H), 4.35-4.19 (m, 2H), 3.61 (dt, J=20.7, 10.3 Hz, 1H), 3.24-3.00 (m,4H), 2.60 (d, J=14.5 Hz, 1H), 2.19 (s, 1H), 1.87 (d, J=4.9 Hz, 1H), 1.64(s, 3H), 1.26 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of(R)-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-((E)-prop--en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanoicacid [24b]

24a (0.15 g, 0.38 mmol, 1.0 equiv) was dissolved in THF (4 mL), MeOH (1mL) and water (1 mL). LiOH.H₂O (0.024 g, 0.57 mmol, 1.5 equiv) was addedand the reaction mixture was stirred at room temperature for 2 hours.The reaction mixture was poured to water, acidified by 1.0 N HCl aqueoussolution up to pH 4 to 5 and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated to affordproduct 24b (0.11 g, 78% yield). LCMS (m/z): 352.2 [M+H]. ¹H NMR (400MHz, DMSO) δ 14.04 (s, 1H), 7.67 (s, 1H), 7.62-7.54 (m, 1H), 7.47 (s,2H), 6.51-6.34 (m, 1H), 4.76 (s, 1H), 3.62 (dt, J=16.9, 10.3 Hz, 1H),3.19 (dd, J=17.4, 9.7 Hz, 1H), 3.13 (s, 3H), 2.56 (s, 1H), 2.16 (dd,J=11.8, 6.9 Hz, 1H), 1.88 (dd, J=48.3, 43.2 Hz, 3H), 1.60 (s, 3H).

Step 3. Synthesis of(2R)-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-((E)-prop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[24c]

24b (0.11 g, 0.3 mmol, 1.0 equiv) was dissolved in THF (10 mL). N-methylmorpholine (0.15 g, 1.5 mmol, 5.0 equiv), HOBT (0.048 g, 0.36 mmol, 1.2equiv), O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.071 g, 0.6 mmol,2.0 equiv), EDC.HCl (0.086 g, 0.45 mmol, 1.5 equiv) were added and thereaction mixture was stirred at room temperature for 24 hours. Thereaction mixture was quenched with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated to afford product 24c (0.11 g, 78% yield). LCMS (m/z):450.4 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.44 (s, 1H), 7.67-7.61 (m, 1H),7.59-7.52 (m, 1H), 7.49-7.39 (m, 2H), 6.48-6.31 (m, 1H), 4.96 (d, J=8.9Hz, 1H), 4.63 (s, 1H), 4.16-4.02 (m, 1H), 3.65-3.42 (m, 2H), 3.14 (dd,J=17.2, 8.5 Hz, 1H), 3.02 (t, J=12.6 Hz, 3H), 2.72-2.60 (m, 1H),2.10-2.00 (m, 1H), 1.82 (dd, J=24.6, 5.3 Hz, 3H), 1.68 (s, 3H), 1.60 (d,J=2.4 Hz, 3H), 1.53 (s, 3H).

Step 4. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-((E)-prop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[24]

24c (0.11 g, 0.23 mmol, 1.0 equiv) was dissolved in methanol (2 mL) anddichloromethane (2 mL). 10% HCl (in IPA) (0.05 mL) was added and thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was quenched with saturated aqueous sodium bicarbonatesolution and extracted with EtOAc. The organic layer was washed withbrine, dried over sodium sulfate and concentrated. The crude residue waspurified by preparative HPLC to afford product 24 (0.02 g, 23% yield).LCMS (m/z): 367.1 [M+H]. ¹H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 9.28(s, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 6.52-6.35 (m,2H), 4.62 (d, J=7.3 Hz, 1H), 3.56 (dd, J=17.0, 10.2 Hz, 1H), 3.13 (dd,J=17.0, 8.1 Hz, 1H), 3.07 (s, 3H), 2.66 (d, J=13.8 Hz, 1H), 2.04 (dd,J=14.0, 8.4 Hz, 1H), 1.87 (d, J=5.2 Hz, 3H), 1.59 (s, 3H).

Example 29. Synthesis of(R)-3-((R)-3-(4-((Z)-1-fluoroprop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[29]

Reagents:

Step 1: PdCl₂(dppf), Cs₂CO₃, 1, 4-dioxane, 110° C. Step 2: NEt₃.3HF,NBS, dichloromethane, 0° C. to room temperature. Step 3: DBU, 85° C.Step 4: LiOH.H₂O, THF, MeOH, water, room temperature. Step 5: NH₂OTHP,EDC.HCl, HOBT, N-Methyl morpholine, THF, room temperature. Step 6: HCl(in IPA), MeOH, dichloromethane, room temperature.

Step 1. Synthesis of (R)-ethyl2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-((Z)-prop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanoate[29a]

(R)-1d-A (0.2 g, 0.47 mmol, 1.0 equiv), (Z)-prop-1-en-1-ylboronic acid(0.053 g, 0.62 mmol, 1.3 equiv) were added in 1, 4-dioxane (4 mL) insealed tube. Cs₂CO₃ (0.47 g, 1.43 mmol, 3.0 equiv) was added and thereaction mixture was degassed for 15 minutes. PdCl₂(dppf) (0.017 g,0.023 mmol, 0.05 equiv) was added and the reaction mixture was stirredat 110° C. for 24 hours. The reaction mixture was filtered throughCelite, washed with EtOAc and the filtrate was concentrated. The cruderesidue was purified by silica gel column chromatography (5%MeOH/dichloromethane) to afford product 29a (0.17 g, 93.7% yield). LCMS(m/z): 380.6 [M+H]. ¹H NMR (400 MHz, DMSO) δ 7.65 (d, J=8.4 Hz, 2H),7.40 (d, J=8.3 Hz, 2H), 6.47 (d, J=13.8 Hz, 1H), 5.92-5.82 (m, 1H),4.80-4.70 (m, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.66-3.57 (m, 1H), 3.23-3.06(m, 4H), 2.60 (dd, J=14.4, 3.2 Hz, 1H), 2.19 (dd, J=14.4, 8.5 Hz, 1H),1.89 (dt, J=7.3, 3.6 Hz, 3H), 1.64 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of (2R)-ethyl3-((5R)-3-(4-(2-bromo-1-fluoropropyl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[29b]

29a (0.17 g, 0.44 mmol, 1.0 equiv) was added in dichloromethane (6 mL)and cooled to 0° C. NEt₃.3HF (0.11 g, 0.66 mmol, 1.5 equiv) and NBS(0.086 g, 0.48 mmol, 1.1 equiv) were added. The reaction mixture wasstirred at room temperature for 24 hours. The reaction mixture wasquenched with water and the mixture was neutralize by NH₄OH. The mixturewas then extracted with dichloromethane. The organic layer was washedwith 1.0 N HCl and saturate aqueous sodium bicarbonate solution, driedover sodium sulfate and concentrated. The crude residue was purified bysilica gel column chromatography (30-50% EtOAc/Hexane) to afford product29b (0.045 g, 20.9% yield). LCMS (m/z): 480.3 [M+H]. ¹H NMR (400 MHz,DMSO) δ 7.77-7.58 (m, 2H), 7.56-7.20 (m, 2H), 5.64 (ddd, J=44.4, 22.9,6.1 Hz, 1H), 4.75 (dd, J=17.0, 6.5 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H),3.68-3.57 (m, 1H), 3.24-3.04 (m, 4H), 2.64-2.53 (m, 1H), 2.19 (dd,J=14.3, 8.5 Hz, 1H), 2.05-1.77 (m, 1H), 1.63 (q, J=6.7 Hz, 3H), 1.25 (d,J=7.1 Hz, 3H).

Step 3. Synthesis of (R)-ethyl3-((R)-3-(4-((Z)-1-fluoroprop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[29c]

29b (0.19 g, 0.39 mmol, 1.0 equiv) was added in DBU (0.06 g, 0.39 mmol,1.0 equiv) and the reaction mixture was stirred at 85° C. for 1 hour.The reaction mixture was quenched with water and extracted withdichloromethane. The organic layer was washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silica gelcolumn chromatography (30% EtOAc/Hexane) to afford product 29c (0.09 g,57.3% yield). LCMS (m/z): 398.3 [M+H]. ¹H NMR (400 MHz, DMSO) δ7.80-7.35 (m, 4H), 5.88 (dt, J=46.1, 6.9 Hz, 1H), 4.76 (d, J=7.5 Hz,1H), 4.27 (q, J=7.1 Hz, 2H), 3.63 (dd, J=17.0, 10.4 Hz, 1H), 3.26-3.09(m, 4H), 2.60 (dd, J=14.4, 3.3 Hz, 1H), 2.19 (dd, J=14.4, 8.5 Hz, 1H),2.04-1.68 (m, 3H), 1.69-1.57 (m, 3H), 1.26 (t, J=7.1 Hz, 3H).

Step 4. Synthesis of(R)-3-((R)-3-(4-((Z)-1-fluoroprop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [29d]

29c (0.09 g, 0.23 mmol, 1.0 equiv) was dissolved in THF (4 mL), MeOH (1mL) and water (1 mL). LiOH.H₂O (0.01 g, 0.23 mmol, 1.0 equiv) was addedand the reaction mixture was stirred at room temperature for 3 hours.The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with water and extracted with EtOAc. The aqueouslayer was acidified by 1.0 N HCl aqueous solution to the pH 4 to 5 andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated to afford product 29d (0.075 g,90.4% yield) which was used without purification in next step. LCMS(m/z): 370.3 [M+H].

Step 5. Synthesis of(2R)-3-((R)-3-(4-((Z)-1-fluoroprop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[29e]

29d (0.075 g, 0.2 mmol, 1.0 equiv) was added in THF (5 mL). N-methylmorpholine (0.1 g, 1.01 mmol, 5.0 equiv), HOBT (0.033 g, 0.24 mmol, 1.2equiv), O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.047 g, 0.41 mmol,2.0 equiv) were added and the reaction mixture was stirred at roomtemperature for 5 minutes. EDC.HCl (0.058 g, 0.3 mmol, 1.5 equiv) wasadded and the reaction mixture was stirred at room temperature for 6hours. The reaction mixture was quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated to afford crude residue. The crude residue waspurified by silica gel column chromatography (40% EtOAc/Hexane) toafford product 29e (0.09 g, 94.7% yield). LCMS (m/z): 385.3 [M-THP]. ¹HNMR (400 MHz, DMSO) δ 11.47 (s, 1H), 7.87-7.53 (m, 4H), 5.88 (dd,J=39.2, 7.1 Hz, 1H), 4.98 (d, J=9.1 Hz, 1H), 4.68 (s, 1H), 4.09-3.97 (m,1H), 3.58 (ddd, J=28.7, 16.3, 11.2 Hz, 2H), 3.21-3.12 (m, 3H), 2.68 (dd,J=8.3, 6.4 Hz, 1H), 2.09 (t, J=6.0 Hz, 1H), 1.74-1.65 (m, 3H), 1.62 (d,J=4.3 Hz, 3H), 1.55 (s, 3H), 1.27-1.20 (m, 3H).

Step 6. Synthesis of(R)-3-((R)-3-(4-((Z)-1-fluoroprop-1-en-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[29]

29e (0.09 g, 0.19 mmol, 1.0 equiv) was dissolved in dichloromethane (4mL) and methanol (1 mL). 10% HCl (in IPA) (0.1 mL) was added and thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was concentrated under reduced pressure, trituratedwith diethyl ether and n-pentane, the solvent was decanted to affordcrude residue.

The crude residue was purified by preparative HPLC purification toafford product 29 as Z-isomer (0.022 g, 30% yield). LCMS (m/z): 385.3[M+H]. ¹H NMR (400 MHz, DMSO) δ 11.27-10.76 (m, 1H), 9.85-9.32 (m, 1H),7.68 (d, J=8.4 Hz, 2H), 7.65-7.56 (m, 2H), 5.88 (dq, J=39.3, 7.0 Hz,1H), 4.70-4.59 (m, 1H), 3.58 (dd, J=16.9, 10.4 Hz, 1H), 3.16 (dd,J=17.1, 8.0 Hz, 1H), 3.05 (d, J=14.1 Hz, 3H), 2.65 (dd, J=13.9, 3.4 Hz,1H), 2.04 (dd, J=14.0, 8.3 Hz, 1H), 1.78 (dd, J=7.1, 2.2 Hz, 3H), 1.58(s, 3H).

31. Synthesis of(R)-3-((R)-3-(4-ethylphenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[31]

Step 1. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-vinylphenyl)-4, 5-dihydroisoxazol-5-yl) propanoate[31a]

(R)-1d-A (0.2 g, 0.48 mmol, 1.0 equiv) was dissolved in 1, 4-dioxane (5mL). 4, 4, 5, 5-Tetramethyl-2-vinyl-1, 3, 2-dioxaborolane (0.1 g, 0.62mmol, 1.3 equiv), Cs₂CO₃ (0.47 g, 1.43 mmol, 3.0 equiv) were added andthe reaction mixture was degassed for 15 minutes.

PdCl₂(dppf) (0.025 g, 0.033 mmol, 0.07 equiv) was added and the reactionmixture was stirred at 100° C. for 24 hours. The reaction mixture wasquenched with water and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated to affordthe desired product 31 (0.16 g, 94% yield). LCMS (m/z): 366.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO) δ 7.60 (dd, J=28.7, 8.3 Hz, 4H), 6.78 (dd, J=17.8,10.9 Hz, 1H), 5.94 (d, J=17.7 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 4.75 (d,J=8.1 Hz, 1H), 4.33-4.16 (m, 2H), 3.67-3.55 (m, 1H), 3.31-2.98 (m, 4H),2.60 (d, J=11.2 Hz, 1H), 2.19 (dd, J=14.4, 8.5 Hz, 1H), 1.64 (s, 3H),1.26 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of ethyl (R)-3-((R)-3-(4-ethylphenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methyl sulfonyl) propanoate [31b]

31a (0.16 g, 0.45 mmol, 1.0 equiv) was dissolved in methanol (5 mL).Pd/C (0.02 g) was added to the solution and the H₂ (gas) was purged intothe reaction mixture at room temperature for 50 minutes. The reactionmixture was filtered through celite bed and the filtrate wasconcentrated to afford a crude residue. The crude residue was purifiedby silica gel column chromatography (20% EtOAc/Hexane) to afford thedesired product 31b (0.13 g, 78% yield). LCMS (m/z): 368.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO) δ 7.58 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H),4.72 (d, J=7.7 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.60 (dd, J=16.9, 10.2Hz, 1H), 3.21-3.11 (m, 4H), 2.64 (dd, J=15.3, 7.8 Hz, 3H), 2.17 (dd,J=14.3, 8.4 Hz, 1H), 1.64 (s, 3H), 1.26 (d, J=1.9 Hz, 3H), 1.19 (t,J=7.6 Hz, 3H).

Step 3. Synthesis of(R)-3-((R)-3-(4-ethylphenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[31]

Ethyl ester 31b was converted to compound 31 by the procedures describedfor the synthesis of 2-A. LCMS (m/z): 355.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO) δ 11.06 (s, 1H), 9.29 (s, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.31 (d,J=8.0 Hz, 2H), 4.60 (s, 1H), 3.56 (dd, J=17.1, 10.3 Hz, 1H), 3.20-3.10(m, 1H), 3.07 (s, 3H), 2.64 (dd, J=14.8, 7.7 Hz, 3H), 2.03 (dd, J=13.4,8.8 Hz, 1H), 1.59 (s, 3H), 1.20 (dd, J=17.7, 10.2 Hz, 3H).

101. Synthesis of(R)-3-((R)-3-(4-ethyl-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[101]

Compound 101 was synthesized by the process of example 31. LCMS (m/z):373.1 [M+H]⁺. ¹H NMR (400 MHz, CD3CN) 1.23 (t, J=7.56 Hz, 3H) 1.69 (s,3H) 2.22 (dd, J=14.18, 8.66 Hz, 1H) 2.55-2.81 (m, 3H) 3.01 (s, 3H) 3.11(dd, J=16.92, 8.36 Hz, 1H) 3.54 (dd, J=16.92, 10.37 Hz, 1H) 4.56-4.87(m, 1H) 7.19-7.47 (m, 3H) 120.(R)-3-((R)-3-(4-ethyl-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[120]

Compound 120 was synthesized by the process of example 31. LCMS (m/z):373.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃CN) 1.24 (t, J=7.63 Hz, 3H) 1.96 (dt,J=4.69, 2.35 Hz, 4H) 2.17 (dd, J=13.89, 3.72 Hz, 1H) 2.63-2.82 (m, 4H)3.01 (s, 3H) 3.19 (ddd, J=17.22, 7.43, 1.96 Hz, 1H) 3.61 (ddd, J=17.22,10.17, 1.96 Hz, 1H) 4.86 (dt, J=7.14, 3.28 Hz, 1H) 6.94-7.23 (m, 2H)7.68 (t, J=8.02 Hz, 1H) 9.35-9.67 (m, 1H)

32. Synthesis of(R)-3-((R)-3-(4-(ethylthio)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[32]

Step 1. Synthesis of ethyl (R)-3-((R)-3-(4-(ethylthio) phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methyl sulfonyl) propanoate [32a]

K₂CO₃ (0.07 g, 0.48 mmol, 1.0 equiv) was dissolved in xylene (4 mL) andcooled to 0° C. Ethanethiol (0.15 g, 2.39 mmol, 5.0 equiv) was addeddrop wise and the reaction mixture was stirred at room temperature for 1hour. (R)-1d-A (0.2 g, 0.48 mmol, 1.0 equiv), Pd₂(dba)₃ (0.022 g, 0.024mmol, 0.05 equiv), xantphos (0.028 g, 0.048 mmol, 0.1 equiv) were addedin xylene (8 mL). The reaction mixture was stirred at room temperaturefor 20 minutes. This solution was added to above potassium thiolate andthe reaction mixture was stirred at reflux temperature for 24 hours. Thereaction mixture was quenched with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated to afford a crude residue. The crude residue was purifiedby silica gel column chromatography (60% EtOAc/Hexane) to afford thedesired product 32a (0.17 g, 86.2% yield). LCMS (m/z): 400.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO) δ 7.60 (t, J=8.6 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H),4.73 (dd, J=15.3, 8.0 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.59 (dd, J=16.9,10.3 Hz, 1H), 3.20-3.11 (m, 4H), 3.07-3.00 (m, 2H), 2.59 (dd, J=14.4,3.2 Hz, 1H), 2.21 (dd, J=10.1, 5.4 Hz, 1H), 1.63 (s, 3H), 1.27 (dd,J=7.2, 1.1 Hz, 3H).

Step 2. Synthesis of(R)-3-((R)-3-(4-(ethylthio)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[32]

Ethyl ester 32a was converted to compound 31 by the procedures describedfor the synthesis of 2-A. LCMS (m/z): 387.4 [M+H]⁺. ¹H NMR (400 MHz,DMSO) δ 11.00 (s, 1H), 9.28 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.37 (d,J=8.5 Hz, 2H), 4.62 (d, J=7.2 Hz, 1H), 3.55 (dd, J=17.0, 10.3 Hz, 1H),3.12 (dd, J=17.0, 8.0 Hz, 1H), 3.04 (dd, J=13.9, 6.6 Hz, 5H), 2.65 (dd,J=14.0, 3.1 Hz, 1H), 2.08-1.99 (m, 1H), 1.59 (s, 3H), 1.26 (t, J=7.3 Hz,3H).

33. Synthesis of (R)-3-((R)-3-(4-(3-fluoropropyl) phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methyl sulfonyl)propanamide [33]

Step 1. Synthesis of ethyl (R)-3-((R)-3-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)-4, 5-dihydroisoxazol-5-yl)-2-methyl-2-(methyl sulfonyl)propanoate [33a]

(R)-1d-A (0.3 g, 0.72 mmol, 1.0 equiv) was dissolved in diethyl amine:N, N-dimethylformamide (5:1) (20 mL). CuI (0.013 g, 0.071 mmol, 0.1equiv), triphenylphosphine (0.037 g, 0.14 mmol, 0.2 equiv) were addedand the reaction mixture was degassed for 15 minutes. PdCl₂(pph₃)₂(0.024 g, 0.035 mmol, 0.05 equiv), prop-2-yn-1-ol (0.06 g, 1.07 mmol,1.5 equiv) were added and the reaction mixture was stirred at 120° C.for 24 hours. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated to afford a crude residue. The crude residuewas purified by silica gel column chromatography (65-70% EtOAc/Hexane)to afford product 33a (0.27 g, 87.1% yield). LCMS (m/z): 394.4 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 7.66 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H),5.39 (t, J=6.0 Hz, 1H), 4.78 (s, 1H), 4.33 (d, J=6.0 Hz, 1H), 4.27 (d,J=7.1 Hz, 1H), 3.61 (s, 1H), 3.27-3.07 (m, 4H), 2.61 (s, 1H), 2.19 (dd,J=14.5, 8.5 Hz, 1H), 1.64 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of ethyl (R)-3-((R)-3-(4-(3-hydroxypropyl) phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methyl sulfonyl) propanoate [33b]

33a (0.27 g, 0.68 mmol, 1.0 equiv) was dissolved in methanol (10 mL).Pd/C (10%) (0.027 g) was added to the solution and the H₂ (gas) waspurged into the reaction mixture at room temperature for 1 hour. Thereaction mixture was filtered through celite bed, washed with methanoland the filtrate was concentrated to afford the desired product 33b (0.2g, 73.5% yield). LCMS (m/z): 398.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 7.58(s, 2H), 7.29 (d, J=8.2 Hz, 2H), 4.79-4.69 (m, 1H), 4.51 (s, 1H), 4.27(q, J=7.1 Hz, 2H), 3.60 (dd, J=16.9, 10.3 Hz, 1H), 3.41 (dd, J=10.4, 6.1Hz, 2H), 3.18-3.16 (m, 1H), 3.14 (s, 3H), 2.68-2.62 (m, 2H), 2.59 (dd,J=14.6, 3.4 Hz, 1H), 2.17 (dd, J=14.4, 8.5 Hz, 1H), 1.77-1.67 (m, 2H),1.64 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).

Step 3. Synthesis of ethyl (R)-3-((R)-3-(4-(3-fluoropropyl) phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methyl sulfonyl) propanoate [33c]

33b (0.15 g, 0.38 mmol, 1.0 equiv) was dissolved in dichloromethane (18mL) and cooled to −78° C. DAST (0.12 g, 0.75 mmol, 2.0 equiv) was addeddrop wise and the reaction mixture was stirred at room temperature for 3hours. The reaction mixture was quenched with saturated aqueous sodiumbicarbonate solution and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated to afforda crude residue. The crude residue was purified by silica gel columnchromatography (30-35% EtOAc/Hexane) to afford the desired product 33c(0.1 g, 49.8% yield). LCMS (m/z): 400.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ7.59 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 4.73 (d, J=7.5 Hz, 1H),4.51 (t, J=6.0 Hz, 1H), 4.39 (t, J=6.0 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H),3.65-3.55 (m, 1H), 3.21-3.09 (m, 4H), 2.74-2.69 (m, 1H), 2.59 (d, J=14.7Hz, 2H), 2.18 (dt, J=15.8, 6.5 Hz, 2H), 2.00 (d, J=5.8 Hz, 1H), 1.64 (s,3H), 1.26 (dd, J=8.7, 5.5 Hz, 3H).

Step 4. Synthesis of (R)-3-((R)-3-(4-(3-fluoropropyl) phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methyl sulfonyl)propanamide [33]

Ethyl ester 33ca was converted to compound 33 by the proceduresdescribed for the synthesis of 2-A. LCMS (m/z): 387.5 [M+H]⁺. ¹H NMR(400 MHz, DMSO) δ 11.15-10.72 (m, 1H), 9.51-9.09 (m, 1H), 7.58 (d, J=7.8Hz, 2H), 7.32 (d, J=7.7 Hz, 2H), 4.63 (s, 1H), 4.51 (t, J=5.7 Hz, 1H),4.40 (t, J=6.0 Hz, 1H), 3.55 (dd, J=17.1, 10.0 Hz, 1H), 3.20-3.11 (m,1H), 3.07 (s, 3H), 2.76-2.69 (m, 2H), 2.65 (d, J=14.9 Hz, 1H), 2.00 (dd,J=29.9, 21.4 Hz, 3H), 1.58 (s, 3H).

34. Synthesis of (R)-3-((R)-3-(4-(4-fluorobutyl) phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methyl sulfonyl)propanamide [34]

Compound 34 was synthesized by the process of example 33. LCMS (m/z):401.4 [M+H]+. ¹H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 9.29 (s, 1H), 7.57(d, J=7.8 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 4.60 (s, 1H), 4.52 (s, 1H),4.40 (s, 1H), 3.55 (s, 1H), 3.19-3.00 (m, 4H), 2.65 (d, J=6.6 Hz, 3H),2.08-1.98 (m, 1H), 1.63 (d, J=31.6 Hz, 7H).

39. Synthesis of Synthesis of(R)—N-hydroxy-3-((R)-3-(4-((3-(2-hydroxypropan-2-yl) cyclobutyl)ethynyl) phenyl)-4, 5-dihydroisoxazol-5-yl)-2-methyl-2-(methyl sulfonyl)propanamide [39A & 39B]

39A (0.065 g, 21.9% yield). LCMS (m/z): 463.6 [M+H]⁺. ¹H NMR (400 MHz,DMSO) δ 11.07 (s, 1H), 9.29 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.47 (d,J=8.4 Hz, 2H), 4.64 (d, J=6.7 Hz, 1H), 4.25 (s, 1H), 3.62-3.51 (m, 1H),3.19-3.09 (m, 2H), 3.07 (s, 3H), 2.66 (d, J=13.5 Hz, 1H), 2.46 (d, J=8.0Hz, 1H), 2.37 (dd, J=18.1, 8.3 Hz, 2H), 2.08-1.95 (m, 3H), 1.59 (s, 3H),1.01 (s, 6H). 39B (0.055 g, 18.6% yield). LCMS (m/z): 463.6 [M+H]⁺. ¹HNMR (400 MHz, DMSO) δ 11.21-10.94 (m, 1H), 9.45-9.16 (m, 1H), 7.61 (d,J=8.4 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 4.63 (s, 1H), 4.23 (s, 1H), 3.56(dd, J=17.1, 10.5 Hz, 1H), 3.14 (dd, J=17.2, 7.8 Hz, 1H), 3.06 (s, 3H),3.02 (d, J=8.2 Hz, 1H), 2.65 (d, J=14.6 Hz, 1H), 2.16 (s, 1H), 2.15 (d,J=5.9 Hz, 3H), 2.11-2.00 (m, 3H), 1.58 (s, 3H), 0.97 (s, 6H).

Compounds 40-122 was Synthesized by One of the Following Methods MethodA Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(thiophen-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[91]

Step 1. Synthesis of (R)-benzyl2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(thiophen-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanoate[91b]

To a mixture of (R)-benzyl3-((R)-3-(4-bromophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate(91a, 70 mg, 0.146 mmol) and thiophen-3-ylboronic acid (37.3 mg, 0.291mmol) in DME (2 mL) was added PdCl₂(dppf). CH₂Cl₂ adduct (11.90 mg,0.015 mmol), followed by Na₂CO₃ (46.3 mg, 0.437 mmol) and water (0.5mL). The resultant mixture was sealed and was stirred at 110° C. for 10min using microwave reactor. The reaction mixture was diluted withEtOAc. The organic layer was separated, dried over Na₂SO₄, andconcentrated. The crude residue was purified byu silica gel columnchromatography (EtOAc/heptane, 10 to 80%) to give product 91 b (29 mg,41.2% yield). LCMS: m/e: 484.3 [M+H]⁺.

Step 2: Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(thiophen-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[91]

Compound 91 could be synthesized from 91a by the procedure of 2-A or bythe following one step procedure.

To a mixture of 91a and NH₂OH (0.091 mL, 50% in water, 2.89 mmol) in THF(0.15 mL) and MeOH (0.30 mL) was added NaOH (23.16 mg, 0.579 mmol). Theresultant mixture was stirred at rt for 1 hour. The mixture was purifiedon reverse phase HPLC to afford product 91 (9 mg, 0.021 mmol, 36.5%yield). LCMS: m/e: 409.3 [M+H]⁺, ¹H NMR (400 MHz, DMSO) 1.58 (s, 4H)1.93-2.14 (m, 2H) 2.59-2.74 (m, 2H) 3.05 (s, 3H) 3.09-3.23 (m, 2H)3.49-3.67 (m, 1H) 4.50-4.80 (m, 2H) 7.66 (d, J=7.68 Hz, 4H) 7.80 (s, 2H)7.88-8.08 (m, 1H) 9.14-9.39 (m, 1H) 10.84-11.19 (m, 1H)

Method B Synthesis of(R)—N-hydroxy-3-((R)-3-(4-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide[81]

Step 1. Synthesis of (R)-benzyl2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanoate[81a]

A solution of 91a (140 mg, 0.29 mmol, 1.0 equiv), pinacol diboron (81mg, 0.32 mmol, 1.1 equiv) and potassium acetate (86 mg, 0.87 mmol, 3.0equiv) in 1, 4-dioxane (1.5 mL) was degassed for 5 minutes. PdCl₂(dppf).CH₂Cl₂ (12 mg, 0.015 mmol, 0.05 equiv) was added to the reactionmixture. The resulting reaction mixture was stirred at 100° C. for 2hours. The reaction mixture was quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (20-75% EtOAc in Hexane) to afford 81a (145 mg, 94%yield). LCMS (m/z): 528.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 7.82(d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.42-7.34 (m, 5H), 5.32 (d,J=12.1 Hz, 1H), 5.27 (d, J=12.1 Hz, 1H), 4.79 (qd, J=8.3, 3.5 Hz, 1H),3.39 (dd, J=16.7, 10.3 Hz, 1H), 3.01-2.95 (m, 1H), 2.97 (s, 3H), 2.61(dd, J=14.2, 3.4 Hz, 1H), 2.41 (dd, J=14.2, 8.4 Hz, 1H), 1.55 (s, 3H),1.35 (s, 12H).

Step 2: Synthesis of (R)-benzyl3-((R)-3-(4-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[81 b]

81a (60 mg, 0.114 mmol, 1.0 equiv), 2-(4-bromopyridin-2-yl)propan-2-ol(0.32 mmol, 1.2 equiv) and potassium acetate (60 mg, 0.284 mmol, 2.5equiv) were dissolved in THF (0.6 mL)/H₂O (0.3 mL) and degassed for 5minutes. PdCl₂(dppf). CH₂Cl₂ (10 mg, 0.012 mmol, 0.1 equiv) was added tothe reaction mixture. The resulting reaction mixture was stirred at 65°C. overnight. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (25-100% EtOAc in Hexane) to give product (32 mg, 52%yield). LCMS (m/z): 537.3 [M+H]⁺.

Step 3. Synthesis of(R)—N-hydroxy-3-((R)-3-(4-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide[81]

Compound 81 was synthesized from 81b by the procedure described for thesynthesis of 91 step 2. LCMS (m/z): 462.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) 11.04 (s, 1H), 8.63 (d, J=5.4 Hz, 1H), 8.20-8.12 (m, 1H), 7.99(d, J=7.7 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 4.76-4.61 (m, 1H), 3.63 (dd,J=17.0, 10.4 Hz, 1H), 3.20 (dd, J=17.1, 8.1 Hz, 1H), 3.05 (s, 3H),2.72-2.63 (m, 1H), 2.06 (dd, J=13.8, 8.6 Hz, 1H), 1.59 (s, 3H), 1.55 (s,6H).

Method C: Synthesis of(R)—N-hydroxy-2-methyl-3-((R)-3-(4-(6-methylpyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-(methylsulfonyl)propanamide[67]

Compound 67a was synthesized from 91a by the procedures described in thesynthesis of 2-A. A mixture 67a (40 mg, 0.082 mmol),(6-methylpyridin-3-yl)boronic acid (22.39 mg, 0.163 mmol), PdCl₂(dppf).CH₂Cl₂ adduct (6.67 mg, 8.17 μmol) and Na₂CO₃ (26.0 mg, 0.245 mmol) inDME (3 mL) was stirred at 110° C. for 15 min using microwave reactor.The reaction mixture was diluted water (10 ml) and extracted with EtOAc.The organic layer was washed with water. dried on Na₂SO₄, filtered, andconcentrated. The crude material was dissolved in MeOH (5.0 mL) followedby 4.0 N HCl in dioxane (1.0 mL). The resultant mixture was stirred for25 min and then was concentrated. The residue was purified by reversephase HPLC to give product 67 (22 mg, 61.2% yield). LCMS (m/z): 418.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) ppm 1.50-1.67 (m, 3H) 2.05 (dd,J=13.99, 8.41 Hz, 1H) 2.59-2.74 (m, 4H) 2.99-3.10 (m, 3H) 3.18 (dd,J=17.07, 8.12 Hz, 2H) 3.61 (dd, J=16.99, 10.39 Hz, 3H) 4.66 (d, J=7.09Hz, 2H) 7.64-7.97 (m, 5H) 8.43 (d, J=7.63 Hz, 1H) 8.99 (d, J=1.61 Hz,1H) 11.04 (br. s., 1H)

40. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-(2-hydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide[40]

Compound 40 was synthesized by method A. LCMS (m/z): 447.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 1.89-2.14 (m, 1H) 2.59-2.71 (m,1H) 2.75 (t, J=6.94 Hz, 2H) 3.05 (s, 3H) 3.18 (d, J=8.17 Hz, 1H)3.47-3.73 (m, 3H) 4.64 (br. s., 2H) 7.31 (d, J=8.12 Hz, 2H) 7.61 (d,J=8.12 Hz, 2H) 7.65-7.80 (m, 4H) 9.25 (s, 1H) 11.03 (s, 1H)

41. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 41 was synthesized by method A. LCMS (m/z): 433.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 2.05 (dd, J=14.06, 8.34 Hz, 1H)2.66 (dd, J=14.06, 3.35 Hz, 1H) 3.05 (s, 3H) 3.16 (dd, J=17.04, 8.09 Hz,1H) 3.59 (dd, J=16.95, 10.29 Hz, 1H) 4.53 (s, 2H) 4.63 (dd, J=10.27,3.13 Hz, 1H) 5.07-5.42 (m, 1H) 7.41 (d, J=8.12 Hz, 2H) 7.61-7.84 (m, 6H)9.26 (s, 1H) 11.04 (s, 1H) 42. Synthesis of(R)-3-((R)-3-(4-(3-fluoropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[42]

Compound 42 was synthesized by method A. LCMS (m/z): 422.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.05 (s, 1H), 8.69 (d, J=2.6 Hz, 1H), 8.54 (d,J=5.6 Hz, 1H), 7.84-7.76 (m, 4H), 7.69 (dd, J=7.0, 5.0 Hz, 1H), 4.68(ddt, J=11.8, 8.6, 3.7 Hz, 1H), 3.63 (dd, J=17.0, 10.4 Hz, 1H), 3.20(dd, J=17.1, 8.2 Hz, 1H), 3.06 (s, 3H), 2.76-2.66 (m, 1H), 2.13-2.04 (m,1H), 1.61 (s, 3H).

43.(R)-3-((R)-3-(4-(2H-1,2,3-triazol-2-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[43]

LCMS (m/z): 394.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 11.04 (s, 1H), 9.26(s, 1H), 8.16 (s, 2H), 8.10 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H),4.64 (dd, J=13.4, 5.3 Hz, 1H), 3.61 (dd, J=17.0, 10.4 Hz, 1H), 3.20 (dd,J=17.1, 8.2 Hz, 1H), 3.05 (s, 3H), 2.71-2.64 (m, 1H), 2.05 (dd, J=14.0,8.5 Hz, 1H), 1.59 (s, 3H).

45. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 45 was synthesized by method A. LCMS (m/z): 461.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.04 (d, J=6.11 Hz, 3H) 1.59 (s, 3H)1.95-2.16 (m, 1H) 2.68 (s, 3H) 3.05 (s, 3H) 3.12-3.22 (m, 2H) 3.51-3.69(m, 2H) 3.73-3.93 (m, 1H) 4.48-4.71 (m, 1H) 7.29 (d, J=8.17 Hz, 2H)7.53-7.82 (m, 6H) 11.03 (s, 1H)

46. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-((S)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 46 was synthesized by method A. LCMS (m/z): 461.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.04 (d, J=6.11 Hz, 3H) 1.59 (s, 3H) 2.05(dd, J=14.18, 8.22 Hz, 1H) 2.54-2.76 (m, 3H) 2.97-3.08 (m, 3H) 3.16 (dd,J=17.02, 8.12 Hz, 1H) 3.59 (dd, J=16.92, 10.27 Hz, 7H) 3.77-3.93 (m, 2H)4.51-4.74 (m, 1H) 7.29 (d, J=8.12 Hz, 2H) 7.54-7.82 (m, 6H) 11.04 (br.s., 1H)

47. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)propanamide

Compound 47 was synthesized by method C. LCMS (m/z): 502.5 [M+H]+. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 1.93-2.16 (m, 1H) 2.60-2.74 (m,1H) 3.05 (s, 3H) 3.08-3.22 (m, 4H) 3.54-3.70 (m, 3H) 3.84-4.05 (m, 2H)4.39 (br. s., 2H) 4.56-4.78 (m, 1H) 7.43-7.97 (m, 8H) 9.06-9.38 (m, 1H)9.69-10.06 (m, 1H) 11.04 (s, 1H)

48. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-(2-methoxyethoxy)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 48 was synthesized by method C. LCMS (m/z): 477.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 2.06 (d, J=8.41 Hz, 1H) 2.65(br. s., 1H) 3.05 (s, 3H) 3.15 (dd, J=17.04, 8.09 Hz, 1H) 3.52-3.63 (m,1H) 3.63-3.72 (m, 2H) 4.05-4.24 (m, 2H) 4.49-4.76 (m, 1H) 7.03 (d,J=8.75 Hz, 2H) 7.47-7.81 (m, 6H) 9.08-9.41 (m, 1H) 11.03 (s, 1H)

49. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-((R)-1-hydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 49 was synthesized by method C. LCMS (m/z): 447.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.19-1.40 (m, 3H) 1.50-1.66 (m, 3H) 1.93-2.13(m, 1H) 2.57-2.77 (m, 2H) 3.05 (s, 3H) 3.10-3.24 (m, 2H) 3.50-3.74 (m,1H) 4.52-4.68 (m, 1H) 4.69-4.85 (m, 1H) 4.99-5.38 (m, 1H) 7.30-7.54 (m,2H) 7.58-7.90 (m, 5H) 9.02-9.48 (m, 1H) 10.92-11.17 (m, 1H)

50. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-(2-hydroxyethoxy)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 50 was synthesized by method C. LCMS (m/z): 463.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 2.04 (dd, J=14.04, 8.36 Hz, 1H)2.66 (dd, J=13.96, 3.35 Hz, 1H) 3.05 (s, 3H) 3.15 (dd, J=16.99, 8.14 Hz,2H) 3.58 (dd, J=16.97, 10.32 Hz, 2H) 3.72 (t, J=4.96 Hz, 2H) 4.02 (t,J=4.99 Hz, 2H) 4.46-4.72 (m, 1H) 7.03 (d, J=8.80 Hz, 2H) 7.59-7.79 (m,6H) 11.03 (s, 1H)

51.(2R)—N-hydroxy-3-((5R)-3-(4′-(2-hydroxy-1-methoxypropan-2-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide[51]

Compound 51 was synthesized by method A. LCMS (m/z): 491.2 [M+H]+. ¹HNMR (400 MHz, DMSO-d₆) 11.06 (s, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.72 (d,J=8.5 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 4.68-4.62(m, 1H), 3.61 (dd, J=16.9, 10.3 Hz, 1H), 3.45-3.35 (m, 2H), 3.24 (s,3H), 3.18 (dd, J=17.0, 8.1 Hz, 1H), 3.07 (s, 3H), 2.68 (dd, J=14.2, 3.6Hz, 1H), 2.10-2.04 (m, 1H), 1.61 (s, 3H), 1.43 (s, 3H).

56. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-((S)-1-hydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 56 was synthesized by method C. LCMS (m/z): 447.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.27-1.38 (m, 3H) 1.97-2.14 (m, 1H) 2.62-2.73(m, 1H) 2.98-3.08 (m, 3H) 3.10-3.22 (m, 2H) 3.51-3.67 (m, 2H) 4.54-4.69(m, 1H) 4.70-4.82 (m, 1H) 5.08-5.29 (m, 1H) 7.32-7.49 (m, 2H) 7.60-7.67(m, 2H) 7.68-7.82 (m, 3H)

57. Synthesis of(R)—N-hydroxy-3-((R)-3-(3′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 57 was synthesized by method C. LCMS (m/z): 433.4 [M+H]+. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 1.92-2.16 (m, 1H) 2.58-2.73 (m,1H) 3.05 (s, 3H) 3.11-3.22 (m, 2H) 3.48-3.59 (m, 1H) 4.56 (s, 2H)4.59-4.72 (m, 1H) 7.24-7.37 (m, 1H) 7.37-7.49 (m, 1H) 7.73 (d, J=4.11Hz, 6H) 10.88-11.18 (m, 1H)

58. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)propanamide

Compound 58 was synthesized by method C. LCMS (m/z): 481.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.51-1.68 (m, 3H) 1.90-2.18 (m, 2H) 2.59-2.78(m, 2H) 3.05 (s, 3H) 3.10-3.20 (m, 1H) 3.25 (s, 4H) 3.53-3.74 (m, 1H)4.54-4.79 (m, 1H) 7.70-7.82 (m, 2H) 7.82-7.90 (m, 2H) 7.92-8.12 (m, 4H)9.12-9.37 (m, 1H) 10.93-11.13 (m, 1H) 59. Synthesis of(R)-3-((R)-3-(2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide

Compound 59 was synthesized by method C. LCMS (m/z): 451.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.44-1.66 (m, 3H) 2.05 (dd, J=14.06, 8.34 Hz,1H) 2.40-2.53 (m, 4H) 2.66 (dd, J=14.04, 3.33 Hz, 27H) 2.99-3.07 (m, 2H)3.16 (dd, J=17.02, 8.12 Hz, 1H) 3.59 (dd, J=16.97, 10.27 Hz, 1H)3.74-3.87 (m, 2H) 4.63 (dd, J=10.17, 3.28 Hz, 1H) 6.80-7.05 (m, 2H)7.42-7.77 (m, 6H) 9.01-9.09 (m, 1H) 11.04 (s, 1H)

60. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-((R)-2-hydroxy-3-methoxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide[60]

Compound 60 was synthesized by method A. LCMS (m/z): 491.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.06 (s, 1H), 9.29 (s, 1H), 7.75 (d, J=8.5 Hz,2H), 7.72 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz,2H), 4.69-4.62 (m, 1H), 3.81 (dd, J=7.7, 5.0 Hz, 1H), 3.60 (dd, J=17.0,10.4 Hz, 1H), 3.27 (s, 3H), 3.26-3.23 (m, 2H), 3.18 (dd, J=17.0, 8.1 Hz,1H), 3.07 (s, 3H), 2.78 (dd, J=13.6, 4.7 Hz, 1H), 2.68 (d, J=14.1 Hz,1H), 2.61 (dd, J=13.6, 7.7 Hz, 1H), 2.09-2.03 (m, 2H), 1.60 (s, 3H).

61. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-((R)-2-hydroxypropoxy)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 61 was synthesized by method C. LCMS (m/z): 477.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.15 (d, J=6.26 Hz, 3H) 1.59 (s, 3H)1.93-2.14 (m, 1H) 2.54-2.74 (m, 1H) 3.05 (s, 3H) 3.09-3.24 (m, 2H)3.49-3.67 (m, 1H) 3.75-3.89 (m, 2H) 3.89-4.03 (m, 1H) 4.52-4.76 (m, 1H)7.02 (d, J=8.75 Hz, 2H) 7.49-7.81 (m, 6H) 9.02-9.42 (m, 1H) 10.85-11.19(m, 1H)

62. Synthesis of(R)-3-((R)-3-(4-(but-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[62]

Compound 62 was synthesized by method C. LCMS (m/z): 379.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.04 (s, 1H), 9.28-9.22 (m, 1H), 7.61 (d, J=8.4Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 4.68-4.59 (m, 1H), 3.56 (dd, J=17.0,10.4 Hz, 1H), 3.17-3.09 (m, 1H), 3.06 (s, 3H), 2.67-2.61 (m, 1H),2.47-2.42 (m, 2H), 2.04 (dd, J=14.1, 8.4 Hz, 1H), 1.59 (s, 3H), 1.17 (t,J=7.5 Hz, 3H).

64. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[64]

Compound 64 was synthesized by method A. LCMS (m/z): 472.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.06 (s, 1H), 9.28 (s, 1H), 9.16 (s, 1H), 8.44(d, J=8.2 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.82(d, J=8.4 Hz, 2H), 4.68 (qd, J=8.4, 3.4 Hz, 1H), 3.64 (dd, J=17.0, 10.4Hz, 1H), 3.21 (dd, J=17.2, 8.2 Hz, 1H), 3.07 (s, 3H), 2.75-2.66 (m, 1H),2.08 (dd, J=14.1, 8.4 Hz, 1H), 1.61 (s, 3H).

65. Synthesis of(R)—N-hydroxy-3-((R)-3-(4-(6-(hydroxymethyl)pyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 65 was synthesized by method C. LCMS (m/z): 434.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 2.05 (dd, J=14.01, 8.39 Hz, 1H)2.56-2.75 (m, 1H) 2.99-3.10 (m, 3H) 3.18 (dd, J=17.07, 8.22 Hz, 2H) 3.61(dd, J=17.02, 10.42 Hz, 5H) 4.67 (s, 3H) 7.68 (d, J=8.17 Hz, 1H) 7.76(d, J=8.36 Hz, 2H) 7.80-7.97 (m, 2H) 8.31 (d, J=8.12 Hz, 1H) 8.90 (d,J=2.01 Hz, 1H) 11.04 (s, 1H)

66. Synthesis of(R)—N-hydroxy-3-((R)-3-(4-(6-methoxypyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 66 was synthesized by method C. LCMS (m/z): 434.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 2.05 (dd, J=14.04, 8.41 Hz, 1H)2.66 (dd, J=14.01, 3.45 Hz, 1H) 3.05 (s, 3H) 3.16 (dd, J=17.04, 8.14 Hz,2H) 3.89 (s, 4H) 4.63 (d, J=7.14 Hz, 1H) 6.92 (d, J=8.71 Hz, 1H)7.59-7.85 (m, 4H) 8.06 (dd, J=8.66, 2.59 Hz, 1H) 8.54 (d, J=2.45 Hz, 1H)11.04 (br. s., 1H)

68. Synthesis of(R)—N-hydroxy-2-methyl-3-((R)-3-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-(methylsulfonyl)propanamide

Compound 68 was synthesized by method C. LCMS (m/z): 434.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.58 (s, 3H) 1.92-2.15 (m, 1H) 2.58-2.73 (m,1H) 3.05 (s, 3H) 3.15 (dd, J=17.02, 8.12 Hz, 2H) 4.45-4.76 (m, 1H) 6.48(d, J=9.44 Hz, 1H) 7.67 (s, 3H) 7.87 (dd, J=9.44, 2.64 Hz, 1H) 8.22 (d,J=2.54 Hz, 1H) 11.03 (s, 1H)

69. Synthesis of(R)-3-((R)-3-(4′-(2-cyanopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide

Compound 69 was synthesized by method C. LCMS (m/z): 470.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.45-1.78 (m, 9H) 2.07 (d, J=8.36 Hz, 1H)2.65 (d, J=2.64 Hz, 1H) 3.05 (s, 3H) 3.10-3.25 (m, 2H) 3.50-3.69 (m, 1H)4.51-4.78 (m, 1H) 7.61 (d, J=8.46 Hz, 2H) 7.67-7.84 (m, 5H) 11.04 (s,1H)

70. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide

Compound 70 was synthesized by method C. LCMS (m/z): 472.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 2.06 (dd, J=14.01, 8.39 Hz, 1H)2.67 (dd, J=14.11, 3.30 Hz, 1H) 3.05 (s, 3H) 3.19 (dd, J=17.12, 8.17 Hz,2H) 3.56-3.70 (m, 3H) 4.67 (d, J=7.09 Hz, 1H) 7.80 (d, J=8.41 Hz, 2H)8.03 (d, J=8.41 Hz, 2H) 8.09 (d, J=4.30 Hz, 1H) 8.23 (s, 1H) 8.83 (d,J=5.14 Hz, 1H) 11.04 (s, 1H)

71. Synthesis of(R)-3-((R)-3-(4-(2-ethylpyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide

Compound 71 was synthesized by method C. LCMS (m/z): 432.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.16-1.39 (m, 2H) 1.49-1.66 (m, 2H) 2.09 (s,1H) 2.65 (br. s., 1H) 2.85-2.99 (m, 2H) 3.00-3.10 (m, 2H) 3.20 (dd,J=17.22, 8.17 Hz, 2H) 3.63 (dd, J=16.99, 10.39 Hz, 2H) 4.51-4.81 (m, 2H)7.74-8.13 (m, 4H) 8.71 (d, J=5.58 Hz, 1H) 11.05 (s, 1H)

72. Synthesis of(2R)-3-((5R)-3-(4′-(1,2-dihydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide

Compound 72 was synthesized by method A. LCMS (m/z): 463.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 1.94-2.14 (m, 1H) 2.60-2.74 (m,1H) 3.05 (s, 3H) 3.10-3.22 (m, 2H) 3.41-3.51 (m, 2H) 3.53-3.70 (m, 1H)4.42-4.77 (m, 3H) 7.27-7.50 (m, 2H) 7.72 (d, J=7.68 Hz, 6H) 9.11-9.35(m, 1H) 10.89-11.15 (m, 1H)

73. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-(1-(hydroxymethyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 73 was synthesized by method C. LCMS (m/z): 473.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 0.64-0.91 (m, 4H) 1.59 (s, 3H) 1.92-2.15 (m,1H) 2.57-2.74 (m, 2H) 3.05 (s, 3H) 3.10-3.23 (m, 2H) 3.55 (s, 3H)4.46-4.78 (m, 2H) 7.38 (d, J=8.31 Hz, 2H) 7.51-7.82 (m, 6H) 9.05-9.42(m, 1H) 11.03 (s, 1H)

74. Synthesis of(2R)—N-hydroxy-2-methyl-3-((5R)-3-(4′-(methylsulfinyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-(methylsulfonyl)propanamide[74]

Compound 74 was synthesized by method A. LCMS (m/z): 465.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.07 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.85 (d,J=8.6 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 4.67 (qd,J=8.4, 3.8 Hz, 1H), 3.63 (dd, J=16.9, 10.3 Hz, 1H), 3.20 (dd, J=17.0,8.1 Hz, 1H), 3.08 (s, 3H), 2.80 (s, 3H), 2.69 (dd, J=14.0, 3.5 Hz, 1H),2.08 (dd, J=14.0, 8.4 Hz, 1H), 1.62 (s, 3H).

75. Synthesis of(2R)—N-hydroxy-3-((5R)-3-(4′-(2-hydroxy-1-methoxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamidepropanamide[75]

Compound 75 was synthesized by method A. LCMS (m/z): 477.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆)¹H NMR (500 MHz, DMSO-d₆) 11.06 (s, 1H), 9.29 (s,1H), 7.77 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.3 Hz,2H), 7.40 (d, J=8.3 Hz, 2H), 4.65 (qd, J=8.3, 3.5 Hz, 1H), 4.27-4.22 (m,1H), 3.65-3.53 (m, 2H), 3.44 (dd, J=11.4, 4.5 Hz, 1H), 3.21 (s, 3H),3.22-3.14 (m, 1H), 3.07 (s, 3H), 2.68 (dd, J=14.1, 3.4 Hz, 1H), 2.06(dd, J=13.9, 8.3 Hz, 1H), 1.60 (s, 3H).

76. Synthesis of(2R)—N-hydroxy-2-methyl-3-((5R)-3-(4′-(S-methylsulfonimidoyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-(methylsulfonyl)propanamide[76]

Compound 76 was synthesized by method A. LCMS (m/z): 480.2 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) 11.08 (s, 1H), 8.15 (d, J=8.7 Hz, 2H), 8.10 (d,J=8.8 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 4.72-4.65(m, 1H), 3.73-3.59 (m, 1H), 3.64 (s, 3H), 3.21 (dd, J=17.0, 8.1 Hz, 1H),3.08 (s, 3H), 2.73-2.67 (m, 1H), 2.13-2.05 (m, 1H), 1.62 (s, 3H).

77. Synthesis of(R)-3-((R)-3-(4′-(2H-1,2,3-triazol-2-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[77]

Compound 77 was synthesized by method A. LCMS (m/z): 470.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.04 (s, 1H), 9.26 (s, 1H), 8.15 (s, 2H), 8.12(d, J=8.8 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H), 7.84 (d, J=8.5 Hz, 2H), 7.75(d, J=8.5 Hz, 2H), 4.70-4.58 (m, 1H), 3.61 (dd, J=17.0, 10.3 Hz, 1H),3.18 (dd, J=17.0, 8.2 Hz, 1H), 3.06 (s, 3H), 2.67 (dd, J=14.6, 4.3 Hz,1H), 2.06 (dd, J=14.2, 8.4 Hz, 1H), 1.59 (s, 3H).

78. Synthesis of(R)-3-((R)-3-(4-(pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[78]

Compound 78 was synthesized by method A. LCMS (m/z): 404.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.05 (s, 1H), 8.88-8.79 (m, 2H), 8.19-8.08 (m,2H), 8.03 (d, J=7.9 Hz, 2H), 7.82 (d, J=8.2 Hz, 2H), 4.68 (ddt, J=12.1,8.7, 3.9 Hz, 1H), 3.63 (dd, J=17.0, 10.4 Hz, 1H), 3.19 (dd, J=17.1, 8.1Hz, 1H), 3.05 (s, 3H), 2.68 (dd, J=14.9, 3.6 Hz, 1H), 2.11-2.02 (m, 1H),1.59 (s, 3H).

79. Synthesis of(R)-3-((R)-3-(2′,6′-difluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[79]

Compound 79 was synthesized by method A. LCMS (m/z): 469.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆)¹H NMR (400 MHz, DMSO-d₆) 11.05 (s, 1H), 9.29 (s,1H), 7.74 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 6.89 (d, J=10.1 Hz,2H), 4.72-4.60 (m, 1H), 3.84 (s, 3H), 3.61 (dd, J=17.0, 10.3 Hz, 1H),3.18 (dd, J=17.1, 8.1 Hz, 1H), 3.07 (s, 3H), 2.72-2.66 (m, 1H), 2.07(dd, J=13.7, 8.7 Hz, 1H), 1.60 (s, 3H).

80. Synthesis of(R)-3-((R)-3-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[80]

Compound 80 was synthesized by method A. LCMS (m/z): 452.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.04 (s, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.77 (d,J=8.6 Hz, 2H), 7.73 (d, J=7.4 Hz, 2H), 7.04 (d, J=5.4 Hz, 1H), 4.72-4.58(m, 1H), 3.87 (s, 3H), 3.61 (dd, J=17.0, 10.4 Hz, 1H), 3.17 (dd, J=17.1,8.1 Hz, 1H), 3.05 (s, 3H), 2.67 (dd, J=13.8, 2.8 Hz, 1H), 2.05 (dd,J=14.1, 8.5 Hz, 1H), 1.59 (s, 3H).

82. Synthesis of(R)-3-((R)-3-(4-(3-chloropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[82]

Compound 82 was synthesized by method A. LCMS (m/z): 438.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.04 (s, 1H), 8.75 (s, 1H), 8.60 (d, J=5.0 Hz,1H), 7.78 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.51 (d, J=4.8 Hz,1H), 4.70-4.61 (m, 1H), 3.62 (dd, J=17.0, 10.3 Hz, 1H), 3.18 (dd,J=17.1, 8.1 Hz, 1H), 3.05 (s, 3H), 2.73-2.64 (m, 1H), 2.06 (dd, J=14.2,8.4 Hz, 1H), 1.59 (s, 3H).

83. Synthesis of(R)-3-((R)-3-(4-(4-fluoropyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[83]

Compound 83 was synthesized by method B. LCMS (m/z): 422.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.05 (s, 1H), 8.69 (d, J=2.9 Hz, 1H), 8.15 (d,J=8.6 Hz, 2H), 8.15-8.10 (m, 1H), 7.86 (td, J=8.8, 3.0 Hz, 1H), 7.77 (d,J=8.5 Hz, 2H), 4.67 (ddt, J=11.8, 8.6, 4.0 Hz, 1H), 3.62 (dd, J=17.0,10.4 Hz, 1H), 3.19 (dd, J=17.0, 8.1 Hz, 1H), 3.07 (s, 3H), 2.76-2.64 (m,1H), 2.07 (dd, J=14.0, 8.4 Hz, 1H), 1.61 (s, 3H).

84. Synthesis of(R)—N-hydroxy-3-((R)-3-(4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide[84]

Compound 84 was synthesized by method B. LCMS (m/z): 462.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.05 (s, 1H), 8.85 (s, 1H), 8.28-8.13 (m, 1H),7.84 (d, J=8.0 Hz, 2H), 7.83-7.77 (m, 1H), 7.76 (d, J=8.3 Hz, 2H),4.71-4.58 (m, 1H), 3.62 (dd, J=17.0, 10.3 Hz, 1H), 3.18 (dd, J=17.0, 8.1Hz, 1H), 3.06 (s, 3H), 2.68 (dd, J=13.6, 2.8 Hz, 1H), 2.06 (dd, J=14.0,8.5 Hz, 1H), 1.60 (s, 3H), 1.49 (s, 6H).

85. Synthesis of(R)-3-((R)-3-(4-(3-methylpyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[85]

Compound 85 was synthesized by method B. LCMS (m/z): 418.2 [M+H]+. ¹HNMR (400 MHz, DMSO-d₆) 11.06 (s, 1H), 8.84-8.58 (m, 3H), 7.80 (d, J=8.2Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 4.76-4.62 (m, 1H), 3.64 (dd, J=17.0,10.4 Hz, 1H), 3.26-3.14 (m, 1H), 3.07 (s, 3H), 2.72-2.65 (m, 1H), 2.34(s, 3H), 2.07 (dd, J=14.1, 8.4 Hz, 1H), 1.61 (s, 3H).

86. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-((R)-3-hydroxy-2-methoxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide[86]

Compound 86 was synthesized by method B. LCMS (m/z): 491.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.03 (s, 1H), 9.25 (s, 1H), 7.75 (d, J=8.5 Hz,2H), 7.70 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz,2H), 4.63 (ddt, J=11.6, 8.4, 3.6 Hz, 1H), 3.59 (dd, J=16.9, 10.3 Hz,1H), 3.40-3.23 (m, 2H), 3.26 (s, 3H), 3.16 (dd, J=17.0, 8.1 Hz, 1H),3.05 (s, 3H), 2.85-2.62 (m, 3H), 2.05 (dd, J=14.6, 7.8 Hz, 1H), 1.59 (s,3H).

87. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-(hydroxymethyl)-2′-methyl-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 87 was synthesized by method C. LCMS (m/z): 447.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.15 (s, 2H) 1.59 (s, 3H) 1.99-2.12 (m, 1H)2.22 (s, 3H) 2.60-2.73 (m, 1H) 3.05 (s, 3H) 3.12-3.23 (m, 2H) 3.51-3.66(m, 2H) 3.93-4.11 (m, 1H) 4.49 (s, 2H) 4.56-4.75 (m, 1H) 5.73 (s, 3H)7.09-7.28 (m, 3H) 7.40 (d, J=8.12 Hz, 2H) 7.69 (d, J=8.07 Hz, 2H) 11.04(s, 1H)

88. Synthesis of(R)-3-((R)-3-(2′,6′-difluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[88]

Compound 88 was synthesized by method B. LCMS (m/z): 497.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.04 (s, 1H), 9.25 (s, 1H), 7.83 (d, J=8.5 Hz,2H), 7.71 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 4.71-4.57 (m, 1H),3.85 (q, J=6.5 Hz, 1H), 3.60 (dd, J=17.0, 10.4 Hz, 1H), 3.16 (dd,J=17.0, 8.1 Hz, 1H), 3.05 (s, 3H), 2.75 (dd, J=13.1, 6.8 Hz, 1H), 2.65(m, 2H), 2.05 (dd, J=14.0, 8.4 Hz, 1H), 1.58 (s, 3H), 1.07 (d, J=6.1 Hz,3H).

89. Synthesis of(R)-3-((R)-3-(2′-fluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[89]

Compound 89 was synthesized by method A. LCMS (m/z): 479.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.06 (s, 1H), 9.28 (s, 1H), 7.74 (d, J=8.3 Hz,2H), 7.62 (d, J=7.2 Hz, 2H), 7.38 (m, 1H), 7.34 (m, 1H), 7.22 (t, J=7.6Hz, 1H), 4.73-4.53 (m, 1H), 3.89 (q, J=6.1 Hz, 1H), 3.62 (dd, J=16.9,10.2 Hz, 1H), 3.24-3.13 (m, 1H), 3.07 (s, 3H), 2.77 (dd, J=13.7, 6.8 Hz,1H), 2.73-2.64 (m, 2H), 2.07 (dd, J=14.1, 8.4 Hz, 1H), 1.61 (s, 3H),1.09 (d, J=6.1 Hz, 3H).

90. Synthesis of(R)-3-((R)-3-(2′-methyl-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[90]

Compound 90 was synthesized by method A. LCMS (m/z): 475.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.05 (s, 1H), 9.27 (s, 1H), 7.70 (d, J=8.3 Hz,2H), 7.42 (d, J=8.3 Hz, 2H), 7.14-7.07 (m, 3H), 4.72-4.60 (m, 1H),3.88-3.80 (m, 1H), 3.61 (dd, J=16.9, 10.5 Hz, 1H), 3.24-3.16 (m, 1H),3.07 (s, 3H), 2.74-2.66 (m, 1H), 2.62-2.53 (m, 2H), 2.22 (s, 3H), 2.06(dd, J=15.1, 7.5 Hz, 1H), 1.61 (s, 3H), 1.07 (d, J=6.1 Hz, 3H).

92. Synthesis of(R)—N-hydroxy-3-((R)-3-(4-(isothiazol-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide[92]

Compound 92 was synthesized by method A. LCMS (m/z): 410.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 1.96-2.19 (m, 1H) 2.58-2.76 (m,1H) 3.05 (s, 3H) 3.12-3.25 (m, 1H) 3.49-3.74 (m, 1H) 4.52-4.78 (m, 1H)7.71 (d, J=8.02 Hz, 2H) 7.90 (d, J=8.02 Hz, 2H) 9.10 (s, 1H) 9.19-9.34(m, 1H) 9.45 (s, 1H) 10.88-11.25 (m, 1H)

93. Synthesis of(R)-3-((R)-3-(4′-((2S,3R)-2,3-dihydroxybutyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[93]

Compound 93 was synthesized by method A. LCMS (m/z): 491.4 [M+H]⁺. ¹HNMR (400 MHz, CD3CN) ppm 1.18 (d, J=5.48 Hz, 3H) 1.71 (s, 3H) 1.96 (br.s., 4H) 2.55-2.79 (m, 3H) 2.83-2.99 (m, 2H) 3.11-3.33 (m, 1H) 3.50-3.80(m, 3H) 4.75 (d, J=7.48 Hz, 1H) 7.22-7.47 (m, 2H) 7.51-7.90 (m, 6H)

94. Synthesis of(R)-3-((R)-3-(4′-((S)-1,2-dihydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[94]

Compound 94 was synthesized by method A. LCMS (m/z): 463.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 1.89-2.13 (m, 1H) 2.66 (dd,J=14.01, 3.30 Hz, 1H) 3.05 (s, 3H) 3.16 (dd, J=17.02, 8.12 Hz, 2H)3.41-3.48 (m, 4H) 3.59 (dd, J=16.97, 10.27 Hz, 2H) 4.47-4.76 (m, 2H)7.28-7.87 (m, 8H)

95. Synthesis of(R)-3-((R)-3-(4′-((R)-1,2-dihydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[95]

Compound 95 was synthesized by method A. LCMS (m/z): 463.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 1.92-2.17 (m, 1H) 2.54-2.80 (m,1H) 3.05 (s, 3H) 3.11-3.23 (m, 1H) 3.45 (d, J=5.87 Hz, 2H) 3.51-3.71 (m,1H) 4.57 (s, 3H) 5.13-5.35 (m, 1H) 7.43 (d, J=8.27 Hz, 2H) 7.57-7.86 (m,6H) 9.24 (s, 1H)

96. Synthesis of(2R)-3-((5R)-3-(4′-(1,3-dihydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[96]

Compound 96 was synthesized by method B. LCMS (m/z): 477.2 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) 11.06 (s, 1H), 9.29 (s, 1H), 7.83-7.70 (m, 4H),7.68 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 5.24-5.09 (m, 1H), 4.72(dd, J=7.8, 4.9 Hz, 1H), 4.66 (dd, J=10.2, 3.5 Hz, 1H), 3.66-3.58 (m,1H), 3.58-3.50 (m, 1H), 3.46 (dt, J=10.4, 6.1 Hz, 1H), 3.19 (dd, J=17.0,8.1 Hz, 1H), 3.08 (s, 3H), 2.69 (dd, J=14.1, 3.4 Hz, 1H), 2.11-2.03 (m,1H), 1.87-1.68 (m, 2H), 1.61 (s, 3H).

97. Synthesis of(R)-3-((R)-3-(4-((4-((R)-1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[97]

Compound 97 was synthesized by the process of example 22. LCMS (m/z):487.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) ppm 1.58 (s, 3H) 1.89-2.18 (m,3H) 2.56-2.80 (m, 2H) 3.05 (s, 3H) 3.09-3.23 (m, 2H) 3.36-3.48 (m, 3H)3.48-3.69 (m, 1H) 4.45-4.58 (m, 1H) 4.58-4.98 (m, 2H) 5.19-5.47 (m, 1H)7.25-7.87 (m, 8H)

98. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[98]

Compound 98 was synthesized by the process of example 22. LCMS (m/z):487.3 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) ppm 1.49-1.67 (m, 5H) 1.75-1.89(m, 2H) 2.03 (dd, J=13.62, 7.95 Hz, 1H) 2.63 (dd, J=14.04, 3.28 Hz, 1H)2.78-3.05 (m, 4H) 3.12 (dd, J=17.04, 8.05 Hz, 2H) 3.54 (dd, J=17.02,10.42 Hz, 2H) 3.79 (dt, J=11.51, 4.18 Hz, 2H) 4.63 (dd, J=10.25, 3.06Hz, 1H) 7.35-7.74 (m, 4H) 11.01 (s, 1H)

99. Synthesis of(R)-3-((R)-3-(4-((4-((S)-1,2-dihydroxyethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[99]

Compound 99 was synthesized by the process of example 22. LCMS (m/z):487.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) ppm 1.58 (s, 3H) 1.89-2.18 (m,3H) 2.56-2.80 (m, 2H) 3.05 (s, 3H) 3.09-3.23 (m, 2H) 3.36-3.48 (m, 3H)3.48-3.69 (m, 1H) 4.45-4.58 (m, 1H) 4.58-4.98 (m, 2H) 5.19-5.47 (m, 1H)7.25-7.87 (m, 8H)

100. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(3-(trifluoromethyl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[100]

Compound 100 was synthesized by method A. LCMS (m/z): 440.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.05 (s, 1H), 8.67 (s, 2H), 7.90-7.74 (m, 2H),7.74-7.58 (m, 2H), 4.69 (dtd, J=11.7, 8.4, 3.6 Hz, 1H), 3.69-3.57 (m,1H), 3.20 (dd, J=17.1, 8.1 Hz, 1H), 3.07 (s, 3H), 2.78-2.62 (m, 1H),2.08 (dd, J=14.1, 8.4 Hz, 1H), 1.61 (s, 3H).

102. Synthesis of(R)-3-((R)-3-(2-fluoro-4′-(2-hydroxyethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[102]

Compound 102 was synthesized by method A. LCMS (m/z): 465.4 [M+H]⁺. ¹HNMR (400 MHz, CD3CN) ppm 1.50-1.78 (m, 3H) 1.87-2.07 (m, 10H) 2.75-3.07(m, 4H) 3.17 (dd, J=16.99, 8.49 Hz, 1H) 3.60 (dd, J=16.92, 10.32 Hz, 1H)3.77 (t, J=6.77 Hz, 2H) 4.70-4.98 (m, 2H) 7.38 (d, J=8.12 Hz, 2H)7.44-7.73 (m, 4H).

103. Synthesis of(R)-3-((R)-3-(2-fluoro-4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[103]

Compound 103 was synthesized by method C. LCMS (m/z): 451.0 [M+H]⁺. ¹HNMR (400 MHz, CD3CN) ppm 1.63-1.75 (m, 4H) 1.76-1.85 (m, 2H) 2.61-2.79(m, 3H) 3.02 (s, 3H) 3.09-3.27 (m, 2H) 3.50-3.71 (m, 2H) 4.59-4.70 (m,2H) 4.71-4.87 (m, 1H) 7.42-7.51 (m, 2H) 7.51-7.67 (m, 5H)

104. Synthesis of(R)-3-((R)-3-(4′-(cyanomethyl)-2-fluoro-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[104]

Compound 104 was synthesized by method A. LCMS (m/z): 460.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 4H) 1.94-2.18 (m, 1H) 2.58-2.72 (m,1H) 3.05 (s, 3H) 3.09-3.24 (m, 2H) 3.48-3.68 (m, 1H), 4.10 (s, 3H)4.55-4.78 (m, 1H) 6.51 (s, 1H) 7.47 (d, J=8.17 Hz, 3H) 7.52-7.72 (m, 6H)9.25 (s, 1H) 11.04 (s, 1H)

105. Synthesis of(R)-3-((R)-3-(3-fluoro-4-(6-methoxypyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[105]

Compound 105 was synthesized by method C, LCMS (m/z): 452.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.58 (s, 3H) 1.97-2.18 (m, 2H) 2.61-2.75 (m,2H) 3.05 (s, 4H) 3.10-3.24 (m, 3H) 3.50-3.72 (m, 3H) 3.89 (s, 3H)4.50-4.81 (m, 2H) 6.83-7.07 (m, 2H) 7.50-7.60 (m, 2H) 7.60-7.74 (m, 1H)7.87-8.06 (m, 1H) 8.26-8.52 (m, 1H)

107. Synthesis of(R)-3-((R)-3-(2-fluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[107]

Compound 107 was synthesized by method C. LCMS (m/z): 479.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.04 (d, J=6.11 Hz, 3H) 1.59 (s, 3H)1.95-2.16 (m, 1H) 2.68 (s, 3H) 3.05 (s, 3H) 3.12-3.22 (m, 2H) 3.51-3.69(m, 2H) 3.73-3.93 (m, 1H) 4.48-4.71 (m, 1H) 7.29 (d, J=8.17 Hz, 2H)7.53-7.82 (m, 5H), 9.30 (s, 1H), 11.03 (s, 1H)

108. Synthesis of(R)-3-((R)-3-(3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[108]

Compound 108 was synthesized by method C. LCMS (m/z): 452.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.58 (s, 3H) 1.98-2.16 (m, 1H) 2.56-2.78 (m,1H) 3.05 (s, 3H) 3.09-3.24 (m, 2H) 3.57 (d, J=10.37 Hz, 2H) 4.58-4.79(m, 1H) 6.42 (d, J=7.04 Hz, 1H) 6.57 (s, 1H) 7.47-7.61 (m, 2H) 7.66 (s,1H) 7.78 (d, J=7.09 Hz, 1H) 11.04 (s, 1H)

109. Synthesis of(R)-3-((R)-3-(3-fluoro-4-(6-(hydroxymethyl)pyridin-3-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[109]

Compound 109 was synthesized by method C. LCMS (m/z): 452.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 3H) 1.96-2.17 (m, 2H) 2.58-2.74 (m,2H) 3.05 (s, 3H) 3.12-3.23 (m, 3H) 3.54-3.68 (m, 3H) 4.62 (s, 3H) 7.61(s, 3H) 7.66-7.76 (m, 1H) 7.94-8.13 (m, 1H) 8.58-8.81 (m, 1H)10.88-11.12 (m, 1H)

110. Synthesis of(R)-3-((R)-3-(2-fluoro-4′-(2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[110]

Compound 110 was synthesized by method C. LCMS (m/z): 479.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.31-1.67 (m, 8H) 1.95-2.11 (m, 2H) 2.60-2.78(m, 2H) 3.05 (s, 3H) 3.11-3.22 (m, 2H) 3.47-3.70 (m, 2H) 4.51-4.80 (m,2H) 7.56 (s, 7H) 9.11-9.42 (m, 1H) 10.84-11.15 (m, 1H)

111. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(4-(3-(trifluoromethyl)pyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)propanamide[111]

Compound 111 was synthesized by method B. LCMS (m/z): 472.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.05 (s, 1H), 9.05 (s, 1H), 8.93 (d, J=5.0 Hz,1H), 7.78 (d, J=8.4 Hz, 2H), 7.53 (d, J=5.1 Hz, 1H), 7.48 (d, J=8.2 Hz,2H), 4.75-4.59 (m, 1H), 3.64 (dd, J=17.0, 10.3 Hz, 1H), 3.20 (dd,J=17.1, 8.0 Hz, 1H), 3.07 (s, 3H), 2.73-2.66 (m, 1H), 2.08 (dd, J=14.1,8.4 Hz, 1H), 1.61 (s, 3H).

112. Synthesis of(R)-3-((R)-3-(3-fluoro-4-(2-isopropylpyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[112]

Compound 112 was synthesized by method C. LCMS (m/z): 464.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.02-1.35 (m, 10H) 2.01-2.17 (m, 2H)2.55-2.75 (m, 2H) 2.91-3.27 (m, 8H) 4.01 (d, J=7.09 Hz, 2H) 4.57-4.80(m, 1H) 7.51 (s, 1H) 7.59 (d, J=9.83 Hz, 2H) 7.71 (s, 1H) 7.92-8.11 (m,1H) 8.74 (s, 1H) 11.04 (s, 1H)

113. Synthesis of(R)-3-((R)-3-(2-fluoro-4′-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[113]

Compound 113 was synthesized by method C. LCMS (m/z): 465.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.58 (s, 3H) 2.11 (s, 5H) 2.55-2.73 (m, 2H)3.05 (s, 3H) 3.10-3.22 (m, 2H) 3.77 (s, 5H) 4.54-4.79 (m, 1H) 6.72-6.96(m, 2H) 7.04-7.18 (m, 1H) 7.31-7.41 (m, 1H) 7.44-7.57 (m, 2H) 9.12-9.37(m, 1H) 10.89-11.11 (m, 1H)

114. Synthesis of(R)-3-((R)-3-(2-fluoro-4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[114]

Compound 114 was synthesized by method C. LCMS (m/z): 489.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.94-2.18 (m, 2H) 2.57-2.75 (m, 2H) 3.05 (s,3H) 3.10-3.23 (m, 3H) 3.53-3.69 (m, 1H) 4.58-4.80 (m, 2H) 7.54-7.89 (m,6H) 8.06-8.23 (m, 2H) 9.11-9.33 (m, 1H) 10.93-11.13 (m, 1H)

115. Synthesis of(R)-3-((R)-3-(2,2′-difluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[115]

Compound 115 was synthesized by method C. LCMS (m/z): 497.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) ppm 1.06 (d, J=6.06 Hz, 3H) 1.97-2.15 (m, 1H)2.67 (d, J=12.08 Hz, 4H) 3.05 (s, 3H) 3.20 (s, 2H) 3.52-3.69 (m, 2H)3.76-3.95 (m, 1H) 4.53-4.78 (m, 2H) 7.23 (d, J=7.53 Hz, 2H) 7.37 (s, 1H)7.45-7.65 (m, 3H) 11.04 (s, 1H)

116. Synthesis of(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((R)-3-(2,2′,6′-trifluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)propanamide

Compound 116 was synthesized by method C. LCMS (m/z): 515.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 0.98-1.15 (m, 3H) 1.18-1.31 (m, 1H) 1.99-2.17(m, 2H) 2.59-2.70 (m, 2H) 2.70-2.81 (m, 1H) 3.05 (s, 3H) 3.10-3.22 (m,2H) 3.52-3.66 (m, 1H) 3.76-3.95 (m, 1H) 4.58-4.74 (m, 1H) 4.75-4.86 (m,1H) 7.23-7.37 (m, 2H) 7.48-7.62 (m, 2H) 7.64-7.79 (m, 1H)

117. Synthesis of(R)-3-((R)-3-(3-fluoro-4-(3-fluoropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[117]

Compound 117 was synthesized by method A. LCMS (m/z): 440.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.04 (s, 1H), 8.72 (d, J=1.7 Hz, 1H), 8.60-8.53(m, 1H), 7.70-7.57 (m, 5H), 4.70 (ddd, J=19.0, 8.5, 3.9 Hz, 1H), 3.63(dd, J=17.1, 10.4 Hz, 1H), 3.19 (dd, J=17.2, 8.2 Hz, 1H), 3.06 (s, 3H),2.71-2.63 (m, 1H), 2.14-2.04 (m, 1H), 1.60 (s, 3H).

118. Synthesis of(R)-3-((R)-3-(4-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[118]

Compound 118 was synthesized by method C. LCMS (m/z): 450.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.59 (s, 2H) 1.90-2.19 (m, 1H) 2.57-2.69 (m,3H) 2.98-3.10 (m, 2H) 3.12-3.27 (m, 1H) 3.57-3.70 (m, 2H) 4.49-4.90 (m,2H) 7.44-7.88 (m, 3H) 9.11-9.45 (m, 1H) 11.05 (s, 1H)

119. Synthesis of(R)-3-((R)-3-(2-fluoro-4-(3-fluoropyridin-4-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[119]

Compound 119 was synthesized by method A. LCMS (m/z): 440.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 11.04 (s, 1H), 8.72 (d, J=2.6 Hz, 1H), 8.55 (dd,J=5.0, 1.0 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.77-7.67 (m, 2H), 7.62 (dt,J=8.2, 1.6 Hz, 1H), 4.67 (dtd, J=10.4, 8.4, 3.5 Hz, 1H), 3.65 (ddd,J=17.4, 10.5, 1.7 Hz, 1H), 3.24 (ddd, J=17.4, 8.4, 1.7 Hz, 1H), 3.07 (s,3H), 2.71 (dd, J=14.2, 3.5 Hz, 1H), 2.12-2.05 (m, 1H), 1.61 (s, 3H).

121. Synthesis of(R)—N-hydroxy-3-((R)-3-(4′-((R)-2-hydroxypropyl)-2-methyl-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanamide

Compound 121 was synthesized by method A. LCMS (m/z): 475.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) ppm 1.06 (d, J=6.06 Hz, 4H) 1.88-2.11 (m, 2H)2.26 (s, 4H) 2.55-2.77 (m, 4H) 3.05 (s, 3H) 3.09-3.20 (m, 2H) 3.47-3.65(m, 2H) 3.74-3.97 (m, 1H) 4.51-4.75 (m, 1H) 7.25 (d, J=2.35 Hz, 5H)7.41-7.64 (m, 2H) 10.86-11.13 (m, 1H)

122. Synthesis of(R)-3-((R)-3-(2,6-difluoro-4′-((R)-2-hydroxypropyl)-[1,1′-biphenyl]-4-yl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[122]

Compound 122 was synthesized by method A. LCMS (m/z): 497.3 [M+H]+. ¹HNMR (400 MHz, DMSO-d6) ppm 1.06 (d, J=6.11 Hz, 3H) 1.96-2.20 (m, 2H)2.55-2.76 (m, 3H) 3.05 (s, 3H) 3.08-3.22 (m, 2H) 3.51-3.67 (m, 2H)3.76-3.96 (m, 1H) 4.57-4.81 (m, 1H) 7.34 (q, J=8.15 Hz, 4H) 7.46 (d,J=8.12 Hz, 2H) 11.05 (s, 1H)

123. Synthesis of(R)-3-((R)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[123]

Step 1: Synthesis of (R)-benzyl3-((S)-3-(4-bromo-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[123a]

To a mixture of (R)-benzyl 2-methyl-2-(methylsulfonyl)pent-4-enoate (11g, 39.0 mmol) and (Z)-4-bromo-2-fluoro-N-hydroxybenzimidoyl chloride(11.02 g, 43.6 mmol) in Et₂O (150 mL) at RT was added triethylamine(10.86 mL, 78 mmol). White suspension was formed right after theaddition of the TEA. The reaction mixture was stirred at RT for 3 hours.The reaction mixture was diluted with EtOAc, then filtered. The solutionwas concentrated and the remaining material was purified by silica gelcolumn chromatography (EtOAc/heptane, 5 to 20%). The less polar fractionis the desired diastereomer (3.2 g, 6.42 mmol, 16.48% yield). LCMS:(m/z): 500.1 [M+H]⁺

Step 2: Synthesis of (R)-benzyl3-((R)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[123b]

To a mixture of (R)-benzyl3-((R)-3-(4-bromo-2-fluorophenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate(1.4 g, 2.81 mmol), but-2-ynoic acid (0.354 g, 4.21 mmol), DBU (0.847mL, 5.62 mmol), 1,4-bis(diphenylphosphino)-butane (0.024 g, 0.056 mmol)and bis(triphenylphosphine)palladium dichloride (0.020 g, 0.028 mmol)was added DMSO (14 mL). The resultant mixture was flushed with argon for5 min. The mixture was stirred at 95° C. for 3 h after which, 200 mg ofbut-2-ynoic acid, 15 mg of 1,4-bis(diphenylphosphino)-butane, 10 mg ofpalladium catalyst and 0.3 ml of DBU was added. The flask was flushedagain with argon, and the mixture was stirred at 95° C. for another 2hours. After cooled to RT, the mixture was quenched with water andextracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate and concentrated. The crude material was purified bysilica gel column chromatography, (EtOAc/heptane, 10 to 40%) to giveproduct 123b (570 mg, 44.3% yield). LCMS: (m/z) 458.4 [M+H]⁺.

Step 3. Synthesis of(R)-3-((R)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid [123c]

To a mixture of (R)-benzyl3-((R)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoate(470 mg, 1.027 mmol) in MeOH (3 ml), THF (3 mL) and Water (3 mL) wasadded LiOH (123 mg, 5.14 mmol). The resultant mixture was stirred at 25°C. for 2 h. The reaction mixture was concentrated, diluted with 5 ml ofwater, and was then acidified with 3.0 N aq HCl solution. The resultantmixture was extracted with EtOAc. The organic layer was washed withwater, dried over sodium sulfate and concentrated. The crude materialwas continued to the next step with no further purification. LCMS: (m/z)368.2 [M+H]⁺.

Step 4. Synthesis of(2R)-3-((R)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide[123d]

To(R)-3-((R)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methyl-2-(methylsulfonyl)propanoicacid (377 mg, 1.027 mmol) in DCM (4 mL) was added EDC.HCl (354 mg, 1.849mmol) and HOAT (280 mg, 2.054 mmol) and the resultant mixture wasstirred for 10-20 min. Triethylamine (0.358 mL, 2.57 mmol) was thenadded, followed by O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (241 mg,2.054 mmol). The mixture was stirred at room temperature for 18 hours.The reaction mixture was filtered and the filtrate was purified bysilica gel column chromatography, (EtOAc/heptane, 20 to 75%) to giveproduct 123d (397 mg, 83% yield).

Step 5. Synthesis of(R)-3-((R)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-4,5-dihydroisoxazol-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide[123]

To a solution of 123d (397 mg, 0.851 mmol) in MeOH (20 mL) was added asolution of HCl in dioxane (4.0 M, 3.19 mL, 12.76 mmol). The resultantmixture was stirred at 25° C. for 25 min. The reaction solution was thenconcentrated, and the crude material was purified by silica gel columnchromatography, (MeOH/DCM, 0% to 2.5%) to give product 123 (235 mg,71.5% yield). LC-MS: (m/z) 383.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃CN) 1.69(s, 3H) 1.90-2.02 (m, 1H) 2.02-2.11 (m, 3H) 2.13-2.29 (m, 6H) 2.66 (dd,J=14.18, 3.33 Hz, 1H) 3.01 (s, 3H) 3.18 (ddd, J=17.31, 8.51, 2.01 Hz,1H) 3.60 (ddd, J=17.30, 10.36, 2.03 Hz, 1H) 4.65-4.82 (m, 1H) 7.08-7.31(m, 2H) 7.58-7.79 (m, 1H)

Pharmaceutical Activity Examples

P. aeruqinosa LpxC Inhibition Assay

The P. aeruginosa LpxC protein is produced according to the generalmethod of Hyland et al (Journal of Bacteriology 1997 179, 2029-2037:Cloning, expression and purification of UDP-3-O-acyl-GIcNAc deacetylasefrom Pseudomonas aeruginosa: a metalloamidase of the lipid Abiosynthesis pathway). The LC-MS/MS method for quantitation of LpxCproduct was developed using an Agilent 1200 Capillary HPLC systemcoupled to an Applied Biosystems MDS Sciex 4000QTRAP mass spectrometer.Both instruments are controlled using the Applied Biosystems MDS SciexAnalyst software. LpxC reaction product(UDP-3-O—(R-3-hydroxyacyl)-glucosamine) was produced by hydrolysis ofLpxC substrate catalyzed by P.a. LpxC and purified using reversed phasechromatography on a Phenomenex Luna C18(2) 4.6×50 mm column. An LpxCproduct calibration curve was generated to evaluate the sensitivity anddynamic range of the LC-MS/MS method. Briefly, compounds arepre-incubated with 1 nM P. aeruginosa LpxC for 30 min. at roomtemperature. Reactions are initiated by the addition of 2 μMUDP-3-O—(R-3-hydroxydecanoyl)-GIcNAc. Reactions are conducted in a384-well plate with a total volume of 50 μL in each well containing 50mM Sodium phosphate pH 7.5, 0.005% Trition X-100 for 20 min at roomtemperature. After quenching with 1.8% HOAc (5 μL of a 20% HOAc added toeach well), reaction mixtures are analyzed using the LC-MS/MS method andpeak areas are transformed into product concentration using a LpxCproduct calibration curve. Total activity (0% inhibition control) isobtained from reactions with no inhibitors and 100% inhibition controlis the background using quenched samples before reaction starts. ForIC₅₀ determinations, peak areas are converted to percent inhibition inMicrosoft Excel. Percent inhibition values are plotted vs. log compoundconcentration using XLfit. Data is fit to the four-parameter logisticequation using the non-linear regression algorithm in XLfit to returnthe IC₅₀ and hill slope values.

Bacterial Screens and Cultures

Bacterial isolates were cultivated from −70° C. frozen stocks by twoconsecutive overnight passages at 35° C. in ambient air on 5% blood agar(Remel, Lenexa, Kans.). Quality control and P. aeruginosa ATCC 27853) isfrom the American Type Culture Collection (ATCC; Rockville, Md.) andPAO1 was received from Dr. K. Poole.

Susceptibility Testing

Minimal Inhibitory Concentrations (MICs) were determined by the brothmicrodilution method in accordance with Clinical and LaboratoriesInstitute (CLSI) guidelines. In brief, fresh bacterial overnightcultures were resuspended in sterile saline, adjusted to a 0.5 McFarlandturbidity standard and then diluted 20010-fold in cation adjustedMueller-Hinton Broth II (MHB; Remel BBL) to yield a final inoculum ofapproximately 5×10⁵ colony-forming units (CFU)/mL. Two-fold serialdilutions of compounds were prepared in 100% dimethyl sulfoxide (DMSO)at 100-fold the highest final assay concentration; the resultingdilution series of compounds were diluted 1:10 with sterile water. Tenμl of the drug dilution series in 10% DMSO was transferred to microtiterwells and 90 μl of bacterial suspension was inoculated into the wells.All inoculated microdilution trays were incubated in ambient air at 3735° C. for 20 hours. Following incubation, assay plates were read in amicrotiter plate reader at 600 nm and visually inspected to confirm theMIC endpoint well with the OD value. The lowest concentration of thecompound that prevented visible growth was recorded as the MIC.Performance of the assay was monitored by testing ciprofloxacin againstlaboratory quality control strains in accordance with guidelines of theCLSI.

The P. aeruginosa LpxC inhibitory activity for selected compounds andMIC data for inhibition of growth of P. aeruginosa measured by themethods described above are reported in Table A.

TABLE A PAO1 LCMS PA LpxC MIC Cmpd No. Compound structure [M + H]⁺ IC₅₀(nM) (ug/mL) 1-B 

424.1 [M + 18] <0.0005 1.0 2-A 

365.3 0.0008 0.25 3-B 

403.2 0.001 0.25 4-B 

395.3 0.024 8 5-A 

367.2 0.007 2 6-A 

391.3 0.0007 0.25 8-B 

379.2 0.0005 1 10-B

395.3 <0.0005 1 12-B

383.4 0.002 2 13-B

409.3 0.001 1 14-B

366.4 0.017 8 15-B

392.3 0.004 8 16-B

383.4 [M + 18] 0.0006 1 17-B

409.4 <0.0005 0.5 22

397.2 <0.0005 0.5 23

369.2 <0.0005 0.5 24

367.1 0.0008 0.5 29

385.3 0.0006 0.125 30

419.4 0.0005 0.06 31

355.2 0.001 0.22 32

387.4 0.0009 0.4 33

387.5 0.002 0.5 34

401.4 0.002 0.5 39A

463.6 0.0005 0.5 39B

463.6 0.002 1 40

447.4 0.0005 0.16 41

433.4 0.0005 0.125 42

422.2 0.0005 0.25 43

394.3 0.005 1.4 44

435.4 0.0008 0.5 45

461.3 0.0006 0.16 46

461.3 0.001 0.125 47

502.5 0.0006 0.35 48

477.4 0.001 0.25 49

447.3 0.001 0.25 50

463.4 0.0007 0.18 51

491.2 0.0008 1.4 52

449.9 0.0008 1 53

449.9 0.0005 0.5 54

423.5 0.0007 1 55

444.7 <0.0005 0.5 56

447.3 0.001 0.25 57

433.4 <0.0005 1 58

481.4 <0.0005 0.5 59

451.4 <0.0005 0.35 60

491.3 <0.0005 0.25 61

477.1 0.25 62

379.3 <0.0005 0.33 64

  472.2 [ <0.0005 0.25 65

434.1 <0.0005 1 66

434.0 <0.0005 0.25 67

418.1 <0.0005 0.35 68

434.1 0.002 16 69

470.1 <0.0005 0.71 70

472.0 0.002 8 71

432.1 0.006 0.71 72

463.1 0.35 73

473.1 0.25 74

465.2 <0.0005 0.71 75

477.3 <0.0005 0.5 76

480.2 <0.0005 2 77

470.2 <0.0005 2 78

404.3 <0.0005 1 79

469.2 <0.0005 0.35 80

452.2 1 81

462.2 0.002 16 82

438.2 <0.0005 0.35 83

422.2 <0.0005 1 84

462.3 <0.0005 1 85

418.2 <0.0005 0.5 86

491.3 <0.0005 0.35 87

447.3 <0.0005 0.25 88

497.2 <0.0005 0.25 89

479.2 <0.0005 0.71 90

475.4 <0.0005 0.5 91

409.3 <0.0005 0.125 92

410.3 <0.0005 0.35 93

491.4 <0.0005 2 94

463.1 <0.0005 0.25 95

463.1 <0.0001 0.25 96

477.2 <0.0005 0.5 97

487.3 0.71 98

487.3 0.0006 2 99

487.3 100

440.2 <0.0005 0.25 101

373.1 <0.0005 0.35 102

465.4 <0.0005 0.18 103

451.0 0.0006 0.18 104

460.4 0.0005 0.125 105

452.4 0.001 107

479.4 0.0005 0.25 108

452.4 0.002 8 109

452.4 0.005 110

479.4 <0.0005 0.5 111

472.2 <0.0005 1 112

464.1 <0.0005 1 113

465.1 <0.0005 0.71 114

489.1 <0.0005 32 115

497.3 <0.0005 1 116

515.3 <0.0005 0.5 117

440.2 <0.0005 0.35 118

450.1 0.004 4 119

440.2 <0.0005 0.71 120

373.0 0.0006 0.5 121

475.3 <0.0005 0.5 122

497.3 <0.0005 0.5 123

383.3 <0.0005 0.25

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the following claims.

The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Z is N or CR¹,where R¹ is selected from H, halo, C₁₋₄ alkyl and C₁₋₄ haloalkyl; R² andR³ are both methyl, R⁴ is H or C₁₋₄ alkyl; X is selected from H, halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, and CN; L is selected from —C≡C—, —CR⁵═CR⁶—,—O—, —S—, and a direct bond between A and the ring containing Z; R⁵ andR⁶ are independently selected from H, halo, C₁₋₄ alkyl, and C₁₋₄haloalkyl; and A is halo, CN, or an optionally substituted groupselected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, 5-6 membered heteroaryl containing up to four heteroatomsselected from N, O and S as ring members, and 4-6 membered heterocyclylcontaining up to two heteroatoms selected from N, O and S as ringmembers, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 5-6 membered heteroaryl containing up to four heteroatomsselected from N, O and S as ring members, and 4-6 membered heterocyclylcontaining up to two heteroatoms selected from N, O and S as ringmembers are each optionally substituted with up to three groups selectedfrom halo, hydroxy, CN, R¹⁰, —(CH₂)₀₋₂OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰,—S(O)(NH)R¹⁰, and —(CH₂)₀₋₂N(R¹⁰)₂; where each R¹⁰ is independently H orC₁₋₄ alkyl optionally substituted with one or two groups selected fromamino, hydroxy, C₁₋₄ alkoxy, and CN; and —N(R¹⁰)₂ can represent a 5-6membered heterocyclic ring optionally containing an additionalheteroatom selected from N, O and S as a ring member, and optionallysubstituted with one or two groups selected from oxo, halo, hydroxy,C₁₋₄ alkyl, C₁₋₄ alkoxy, and amino.
 2. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein X is H.
 3. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein X is F.
 4. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is H.
 5. The compound of claim 1 ora pharmaceutically acceptable salt thereof, wherein Z is CH or CF. 6.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein Z is N.
 7. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein A-L- is a group of the formula

where A is an optionally substituted group selected from C₁₋₄ alkyl andC₃₋₆ cycloalkyl, wherein A is optionally substituted with up to threegroups selected from halo, hydroxy, CN, —OR, and —N(R¹⁰)₂ where each R¹⁰is independently H or C₁₋₄ alkyl.
 8. The compound of claim 7 or apharmaceutically acceptable salt thereof, wherein A is C₁₋₄ alkyl orcyclopropyl and is optionally substituted with F, OH, or OMe.
 9. Thecompound of claim 1, which is of the formula:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1, which is selected from:

or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition, comprising: the compound according to claim 9 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 12. A pharmaceutical combination comprising: acompound according to claim 9, or a pharmaceutically acceptable saltthereof, an antibacterially effective amount of a second therapeuticagent, and a pharmaceutically acceptable carrier.
 13. The pharmaceuticalcombination composition according to claim 12, wherein the secondtherapeutic agent is selected from the group consisting of Ampicillin,Piperacillin, Penicillin G, Ticarcillin, Imipenem, Meropenem,Azithromycin, erythromycin, Aztreonam, Cefepime, Cefotaxime,Ceftriaxone, Cefatazidime, Ciprofloxacin, Levofloxacin, Clindamycin,Doxycycline, Gentamycin, Amikacin, Tobramycin, Tetracycline, Tegacyclin,Rifampicin, Vancomycin and Polymyxin.
 14. A method of inhibiting adeacetylase enzyme in a Gram-negative bacterium, comprising: contactingthe Gram-negative bacteria with the compound according to claim 9 or apharmaceutically acceptable salt thereof.
 15. A method for treating asubject with a Gram-negative bacterial infection, comprising:administering to the subject an antibacterially effective amount of thecompound according to claim 9, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 16. The method ofclaim 15, wherein the gram negative bacterial infection is an infectioncaused by Pseudomonas.